The INK4a/ARF locus: role in cell cycle control for renal cell epithelial tumor growth after the Chernobyl accident

Romanenko, Alina; Morell-Quadreny, Luisa; Löpez‐Guerrero, José Antonio; Pellı́n, Antonio; Nepomnyaschy, Valentin; Vozianov, Alexander; Llombart‐Bosch, Antonio

doi:10.1007/s00428-004-1056-7

Cited by 15 publications

(14 citation statements)

References 19 publications

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“…This elevation in p53 is achieved, at least in part, by induction of the ARF gene promoter [7]. The pivotal role of the p14ARF promoter hypermethylation in the pathogenesis of the Ukrainian RCCs from patients living in radiocontaminated areas was recently documented by our group [23]. The possibly mutated oncogenic β-catenin expression in analogue Ukrainian cRCCs might activate the p53 response which, in turn, can enhance the degradation of β-catenin by a negative feedback loop during increased tumor progression [24].…”

Section: Discussionmentioning

confidence: 66%

“…This suggestion is supported by our recent study [23], which showed that the analogue RCCs patients living in the 137 Cs-contaminated areas of Ukraine demonstrate the highest levels of urinary 137 Cs excretion which is known to constitute roughly 90% of internal radioactivity and is concentrated and eliminated through the kidneys [19]. However, it is necessary to note that there were no significant correlations between the above mentioned IHC markers of ECM and TNM stage, nor with other histopathological features of cRCCS.…”

Section: Discussionmentioning

confidence: 69%

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Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

et al. 2006

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The present study was carried out in order to examine molecular alterations of extracellular matrix (ECM), associated with cell-cell communication in conventional (clear-cell) renal cell carcinomas (cRCCs) influenced by persistent long-term, low-dose ionizing radiation (IR) exposure to patients living more than 19 years after the Chernobyl accident in Cesium 137 (137Cs)-contaminated areas of Ukraine. The ECM major components such as fibronectin, laminin, E-cadherin/beta-catenin complexes and p53 tumor suppressor gene protein, and transforming growth factor beta 1 (TGF-beta1) were immunohistochemically (IHC) evaluated in cRCCs from 59 Ukrainian patients, which represented 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. In contrast, a control group of 19 Spanish patients with analogue tumors were also investigated. For IHC evaluation, a tissue microarray technique was used. Decrease or loss and abnormal distribution of fibronectin, laminin, E-cadherin/beta-catenin complexes accompanied by elevated levels of p53 and TGF-beta1 were detected in the Ukrainian cRCCs from 137Cs-contaminated areas with statistically significant differences. Thus, our study suggests that chronic long-term, low-dose IR exposure might result in global remodeling of ECM components of the cRCCs with disruption in peri-epithelial stroma and epithelial basement membranes.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 69%

Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

et al. 2006

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“…Promoter hypermethylation of the tumor suppressor genes on chromosome 9p21 ( INK4A and ARF ) was observed in some renal cell cancers among patients residing in radiation-contaminated areas following the Chernobyl accident 199. In another small series of renal cell cancer patients, somatic mutations in the p53 tumor suppressor gene and the Ras oncogene were not related to gasoline exposure, a postulated renal cancer risk factor, but the majority of the mutations were seen in smokers 200.…”

Section: Genetic Susceptibility and Environmentmentioning

confidence: 99%

Contemporary Epidemiology of Renal Cell Cancer

2008

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We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to TCE has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the VHL gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers. Keywords renal cell cancer; incidence trends; cohort studies; smoking; obesity; hypertension; diet; occupation; genetic polymorphism; somatic mutation Malignant tumors of the kidney account for about 4% of cancer incidence and 2% of cancer mortality in the United States, with over 54,000 new cases and 13,000 deaths having been estimated for 2008. 1 More than 85% of kidney cancers arise in the renal parenchyma, with the remainder arising in the renal pelvis. 2 Renal pelvis cancer is mostly of the transitional cell type and is not the focus of this review. Nearly all cancers originating in the renal parenchyma are adenocarcinomas (renal cell carcinoma), in which clear cell is the predominant subtype. 3 The remainder is made up of the papillary type and other rare histologic types, such as collecting duct and chromophobe carcinomas. 3,4 Distinct morphologic and genetic characteristics have also been described for renal cell carcinoma in familial cancer syndromes. [5][6][7] Descriptive and analytic epidemiologic studies in general have not distinguished the subtypes of renal cell carcinoma, except for studies involving the von Hippel-Lindau (VHL) gene mutation that is seen primarily in the clear cell type. 8 Since the clear cell type comprises 85% to 90% of renal cell carcinoma, 3 the epidemiology of renal cell carcinoma is strongly influenced by that of the clear cell type.* Correspondence: Wong-Ho Chow, National Cancer Institute, 6120 Executive Blvd, EPS 8100, Bethesda, Maryland 20892-7240, USA. choww@mail.nih.gov. NIH Public Access Author ManuscriptCancer J. Author manuscript; available in PMC 2011 April 15. DESCRIPTIVE EPIDEMIOLOGY Incidence patterns and temporal trendsIncidence rates of renal cell carcinoma h...

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“…Interestingly, exposure of workers in nuclear weapons manufacturing facilities to plutonium, for example, has been strongly linked ( P = 0.03) to methylation of the p16 gene in lung adenocarcinomas [40]. Renal cell carcinomas from patients living in areas contaminated by the Chernobyl accident have also shown aberrant hypermethylation of the p16/p14 locus [41]. …”

Section: Discussionmentioning

confidence: 99%

Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies

et al. 2010

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IntroductionMost human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated β-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16). However, HMEC grown in a serum-free medium, spontaneously yield, at low frequency, variant (v) HMEC that are capable of long-term growth and are susceptible to genomic instability. We investigated whether ionizing radiation, which increases breast cancer risk in women, affects the rate of vHMEC outgrowth.MethodsPre-stasis HMEC cultures were exposed to 5 to 200 cGy of sparsely (X- or γ-rays) or densely (1 GeV/amu 56Fe) ionizing radiation. Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated β-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent. Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored. Agent-based modeling, incorporating a simple set of rules and underlying assumptions, was used to simulate vHMEC outgrowth and evaluate mechanistic hypotheses.ResultsCultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated β-galactosidase or p16 expression, than cultures derived from unirradiated cells. As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures. However, the extent of methylation of individual CpG sites in vHMEC samples did not correlate with passage number or treatment. Exposure to sparsely or densely ionizing radiation elicited similar increases in the numbers of vHMEC compared to unirradiated controls. Agent-based modeling indicated that radiation-induced premature senescence of normal HMEC most likely accelerated vHMEC outgrowth through alleviation of spatial constraints. Subsequent experiments using defined co-cultures of vHMEC and senescent cells supported this mechanism.ConclusionsOur studies indicate that ionizing radiation can promote the outgrowth of epigenetically altered cells with pre-malignant potential.

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The INK4a/ARF locus: role in cell cycle control for renal cell epithelial tumor growth after the Chernobyl accident

Cited by 15 publications

References 19 publications

Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

Contemporary Epidemiology of Renal Cell Cancer

Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies

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