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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renewed interest is being directed toward chemoprevention as a means of reducing cancer mortality. To overcome the inherent problems associated with using cancer development as a study end point, there has recently been a great surge of interest in defining the biomarkers associated with specific stages of the carcinogenic process as intermediate end points. We have detailed the evidence supporting the concept of field cancerization, a concept of general importance that is probably applicable to carcinogenesis and chemoprevention at many organ sites in humans, and presented results of tests of the potentially useful biomarkers proliferating cell nuclear antigen and blood group antigen. Because microassay techniques are more readily applicable to small biopsy samples, further expansion of these studies and exploration of panels of additional biomarkers are expected to generate exciting results in the field of chemoprevention.
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PMID:Determination of biomarkers for intermediate end points in chemoprevention trials. 134 62

We examined the activity of spermidine/spermine N1-acetyltransferase (SAT), a rate-limiting enzyme of the biodegradation of polyamines, in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced transitional cell carcinoma (TCC) and melamine-induced papillomatosis of rat bladder, and compared the activity to that of ornithine decarboxylase (ODC). Both activities were higher in both lesions than in control rats. The difference between SAT and ODC activities in cancerous tissue and papillomatosis was not significant. Cells stained for proliferating cell nuclear antigen (PCNA) were abundant in papillomatosis. TCC had areas with much PCNA. The results indicated that an elevation of SAT activity occurs in both reversible and irreversible proliferation of bladder epithelium and could be important in bladder carcinogenesis.
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PMID:Spermidine/spermine N1-acetyltransferase, a new biochemical marker for epithelial proliferation in rat bladder. 136 Apr 68

Numerous nerve fibers containing various neuropeptides are found in gastric mucosa. They play an important role not only in regulation of gastric secretion, motility and microcirculation but also in regeneration and differentiation of gastric mucosa. These nerve fibers are reduced in chronic atrophic gastritis which is considered a lesion closely related to carcinogenesis. We investigated the effect of gastric gastric mucosal denervation (vagotomy) on gastric carcinogenesis by using two experimental rat models in which chronic atrophic gastritis is induced by duodenogastric reflux. At first, following administration of MNNG, vagotomy with duodenogastric reflux enhanced gastric carcinogenesis compared to reflux only. At second, in the model of gastric remnant in which no carcinogenic agent was given, both B-I and B-II gastrectomy with vagotomy showed an increase of carcinoma and/or adenoma at the anastomotic site compared to those without vagotomy. Moreover, in vagotomized groups, there were an increase of labeling index of PCNA positive cells in gastric mucosa and a marked reduction of intramucosal neutral mucin in PAS-Alcian blue staining. These results indicate that the lack of gastric mucosal innervation not only induces the decrease of gastric mucosal cell function and cytoprotection but also enhances the increase of immature cell regeneration.
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PMID:[Effect of gastric mucosal denervation on gastric carcinogenesis]. 136 55

Chemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non-specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF-beta, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested an association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer.
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PMID:Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials. 146 3

Flow cytometry (FCM) is a useful method for clinical research of oncogene products since it can analyze proteins quantitatively which are located at cell surfaces or inside of cells. Oncogene products are now under study by FCM not only as tumor markers but also as functioning proteins in carcinogenesis. The examples of oncogene products analyzed by FCM are ras, myc, p53, myb and fos; those of cell-proliferation-related proteins are Ki-67, PCNA and DNA polymerase alpha. In some diseases the relationship between these proteins and disease classification, stage, pathophysiology, or prognosis have been clarified. Using dual color FCM of H-ras p21 and DNA, we analyzed the expression of H-ras p21 in human multiple myeloma and leukemias and found that H-ras p21 levels in multiple myeloma strongly correlated to the prognosis of patients (p = 0.03). When AML cells were stimulated by adding G-CSF, it was found that many cells proliferated but some were dying. The percentage of dying cells was small in one AML case whose myeloblasts showed increased expression of H-ras p21 by G-CSF stimulation. Together with other papers reviewed, it is conceivable that H-ras p21 expression is related to cell proliferation and inhibition of cell autolysis. Thus FCM is useful in the classification of the role of oncogene products in carcinogenesis in clinical cases.
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PMID:[Application of flow cytometry to the study of hematologic disorders: analysis of oncogene products]. 214 49

A NIH3T3-derived cell clone (NA7) in which human papillomavirus (HPV) 16 early region E6/E7 was inducible by dexamethasone (DXM) under the control of mouse mammary tumor virus long terminal repeat was established. A transforming function for HPV 16 E6/E7 region was analyzed by this established clone. Northern blot hybridization demonstrated that the increased expression of PCNA/cyclin and c-myc at the confluent state in accordance with the induced expression of E6/E7 region by DXM. Although complete transformation was not observed, the saturation density of NA7 was increased by the addition of DXM. The transfection assay using NA7 showed that adenovirus type 5 E1B (Ad5E1B) could cooperate with E6/E7. Furthermore, it was indicated that E7 could also cooperate with adenovirus type 5 E1B as well as with EJ-ras in transforming primary rat embryonal cells. However, E6/E7 could not cooperate with Ad12E1B in both cell systems. In this study, HPV 16 E6/E7 was assumed to have the growth-stimulatory activity in association with some cellular genes and transforming activity by cooperation with some transforming genes. These results suggest that E6/E7 seems to play a major role in the process of human cervical cell carcinogenesis.
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PMID:[The study on in vitro transformation by human papillomavirus type 16 E6/E7 region]. 254 43

The association of the proliferating cell nuclear antigen (PCNA) to DNA synthesis sites during the process of DNA repair, was investigated in human diploid fibroblasts after treatment with different genotoxic agents. For this purpose, confluent cultures were treated with agents that form primarily DNA adducts, such as u.v.-C, 8-methoxypsoralen (8-MOP) and 4,4',6-trimethylangelicin (TMA), or with agents that induce strand breaks, such as X-rays or bleomycin (BLM). Chromatin-associated PCNA was detected with a monoclonal antibody and indirect immunofluorescence labelling. Quantitative analysis was performed by flow cytometry. Not all of the tested agents were able to activate the association of PCNA with chromatin. X-rays, u.v.-C and BLM induced a significant increase in PCNA complex as compared to the control samples. In contrast, 8-MOP and TMA did not show any detectable effect on the levels of associated PCNA, even at post-incubation repair times as long as 10 h. However, these drugs damaged DNA, as shown by the formation of micronucleated cells 48 h after treatment. The lack of PCNA activation was not due to an inhibition of the repair mechanism, since in TMA-treated fibroblasts, subsequent irradiation with u.v.-C induced an increase in PCNA levels comparable to that found in cells treated with u.v.-C alone. These results indicate that PCNA is involved in DNA excision repair of genotoxic agents, but suggest that similar types of lesions may be repaired with alternative pathways not requiring PCNA.
Carcinogenesis 1993 Dec
PMID:Involvement of proliferating cell nuclear antigen in DNA repair after damage induced by genotoxic agents in human fibroblasts. 750 25

Schistosoma haematobium infection is strongly associated with urinary bladder cancer. Although numerous explanations have been proposed for this association, the nature of this relationship remains unresolved. This paper explores the hypothesis that inflammation and elevated cell proliferation play a major role in the development of bladder cancer in infected patients, possibly by increasing the level of genetic instability in the urothelium. The paper details in vivo and in vitro studies being done in our laboratories to test this hypothesis. These studies include population studies in which chromosomal breakage in the bladder of infected individuals is assayed using the micronucleus (MN) test on exfoliated urothelial cells. The approach also includes parallel studies in Vancouver with patients with long-term catheter drainage, a population with many similarities to schistosomiasis patients. In the in vitro studies we are co-incubating bladder cells with activated neutrophils or experimental conditions simulating inflammation. These studies show that inflammatory cells when activated can induce micronuclei in bladder cells and that this response is associated with loci on chromosome 11, a chromosome commonly altered during bladder carcinogenesis. A final approach being used is to assay chromosomal change (MN frequencies and numerical chromosome alterations) and level of proliferation (expression of proliferating cell nuclear antigen) in archival biopsies from schistosomiasis patients. Preliminary results show that a dysregulation of cell proliferation is occurring during cystitis in these patients. The extent to which this alteration affects the level of chromosomal breakage is yet to be determined.
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PMID:Involvement of inflammatory reactions and elevated cell proliferation in the development of bladder cancer in schistosomiasis patients. 751 39

An epizootic of pigmented subcutaneous spindle cell tumors affected nearly 25% of the adult gizzard shad (Dorosoma cepedianum) sampled from Lake of the Arbuckles in central Oklahoma over a 2 year period. Grossly, the tumors were primarily distributed over the head, trunk and fins as superficial raised masses that were almost always darkly pigmented. Histologically, they were located in the dermis, had a variable amount of connective tissue, and consisted of cells in a variety of forms and arrangements. Most tumors were composed of fusiform or spindle cells arranged in wavy bundles, whirling patterns or interwoven fascicles. Pigmentation was attributed to large dense deposits of melanin or to scattered individual melanin-containing cells. Immunohistochemical detection of proliferating cell nuclear antigen revealed a high proliferative activity in the spindle cells. Electron microscopy showed that the tumors were composed of several cell types, including host reactive cells, melanocytes in stages of maturity, and fibroblast-like cells. Tumor cells had neither cell-to-cell junctions nor an external lamina. Although the cell of origin of the tumors was not identified, evidence points toward melanocytes or, possibly, nerve sheath cells. However, an origin from fibroblasts or some other poorly differentiated cell cannot be ruled out. The etiology of the tumors was not determined. Fractionation of lake water and sediment samples followed by GC-MS analysis revealed no carcinogenic compounds. A retroviral etiology is unlikely because assays for reverse transcriptase in tumor homogenates were negative, and no evidence of viral particles was found in specimens examined by electron microscopy.
Carcinogenesis 1995 Jul
PMID:Pigmented subcutaneous spindle cell tumors in native gizzard shad (Dorosoma cepedianum). 754 76

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mice. PGs E2, F2 alpha, I2, the methyl ester of PGE2, dmPGE2, and LTB4 (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF2 alpha and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.
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PMID:Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. 754 86


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