Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis

Arber, Nadir; Hibshoosh, Hanina; Sf, Moss; Sutter, Thomas R.; Zhang, Y; Begg, Melissa D.; Wang, Silu; Weinstein, I. Bernard; Holt, Peter R.

doi:10.1053/gast.1996.v110.pm8608874

Cited by 275 publications

(252 citation statements)

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“…Thus, we found that overexpression of cyclin D1 in esophageal carcinoma , mouse mammary HC11 cells and HCT116 colon carcinoma cells (unpublished studies) was associated with increased expression of the p27 protein. Conversely, derivatives of the SW480-E8 colon carcinoma cell line that expressed an antisense cyclin D1 cDNA displayed decreased levels of both cyclin D1 and p27 (Arber et al, 1996). We also found that ectopic overexpression of cyclin E in the mouse mammary HC11 cell is associated with increased expression of p27 .…”

Section: Discussionmentioning

confidence: 48%

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Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

et al. 1999

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Recent studies have shown that decreased expression of p27 Kip1 is associated with high grade tumors and an unfavorable prognosis in several types of human cancer. To clarify the role of p27 Kip1 in colon cancer, we have overexpressed this protein in the HT29 colon cancer cell line. The derivatives displayed an increase in the p27 Kip1 protein in cyclin E/CDK2 immunoprecipitates and a decrease in cyclin E-associated kinase activity when compared to vector control clones, providing evidence that the overexpressed protein was functional. Clones with a high level of p27 Kip1 displayed partial growth inhibition in monolayer culture and a decrease in plating e ciency, even though they expressed increased levels of the cyclin D1 protein. Using alkaline phosphatase expression as a marker, we found that the p27 Kip1 overexpressor clones displayed a 2 ± 3-fold increase in sensitivity to induction of di erentiation by 2 mM sodium butyrate. In contrast to these results, derivatives of HT29 cells that stably overexpressed p21 Cip1/Waf1 displayed decreased sensitivity to the induction of di erentiation. These ®ndings may explain why decreased levels of p27 Kip1 in certain human cancers is associated with high grade (poorly di erentiated) tumors, and suggest that strategies that increase the level of p27 Kip1 may be useful in cancer therapy.

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Section: Discussionmentioning

confidence: 48%

“…Human colon cancers often show increased expression of the positive acting factors cyclins D1 and E and CDKs (CDK1, 2 and 4) (Bartkova et al, 1994;Arber et al, 1996;Leach et al, 1993;Yamamoto et al, 1995;Zhang et al, 1997). There are also speci®c abnormalities in CKIs.…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

et al. 1999

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“…However, little is known about their presence in precancerous lesions and their significance in tumorigenesis. Overexpression of cyclin DI at early stages of tumour development has been reported recently in several studies on premalignant skin lesions in mice (Robles and Conti, 1995), in human carcinoma in situ of the breast (WeinstatSaslow et al, 1995), in familial adenomatous polyposis of the colon , in premalignant epithelia of patients with head and neck tumours (Izzo et al, 1996) or gastric and oesophageal cancer (Arber et al, 1996). In mice, cyclin Dl was found to be overexpressed in precancerous lesions, including small incipient papillomas, after induction by a two-stage carcinogenesis protocol (Robles and Conti, 1995).…”

Section: Discussionmentioning

confidence: 81%

Abnormal expression of CCNDI and RBI in resection margin epithelia of lung cancer patients

Betticher

Heighway²,

Thatcher³

et al. 1997

Br J Cancer

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Summary Tumours develop through the accumulation of genetic alterations associated with a progressive increase of the malignant phenotype. In lung cancer, chronic exposure of bronchial epithelium to carcinogens in cigarette smoke may lead to multiple dysplastic and hyperplastic lesions scattered throughout the tracheobronchial tree. Little is known about the genetic alterations in such lesions. This study was carried out to examine cyclin Dl (CCND1) and retinoblastoma (RB1) gene expression in the bronchial epithelium of patients with lung cancer. Lung tumours and their corresponding tumour-free resection margins from 33 patients who underwent resection of non-small-cell lung cancer (NSCLC) were examined by immunostaining with monoclonal antibodies against cyclin Dl (DCS-6; Novocastra) and pRb (NCL Rb-1; Novocastra). Examination of the resection margins revealed four carcinomas in situ, 19 hyperplasias and ten sections showing apparently normal bronchial epithelium. A control group of patients, without lung tumours and who had never smoked, revealed no or weak cyclin Dl and positive pRb staining within bronchial epithelia. Increased cyclin Dl and diminished pRb expression were found in 76% (n = 25) and 27% (n = 9) of the resection margins respectively, and in 12% (n = 4) both cyclin Dl and pRb expression were altered. In the corresponding tumours, 48% (n = 16) were normal, while altered expression was found for cyclin Dl in 33% (n = 11), pRb in 27% (n = 9) and both in 9% (n = 3) of cases. It appears that altered expression of cyclin Dl and pRb is an early event in NSCLC development in almost half of cases analysed. Further investigations are needed to determine the significance of immunostaining of bronchial specimens in individuals at risk of lung cancer, with the possibility that the observations are of importance in the early diagnosis of NSCLC.Keywords: non-small-cell lung cancer; carcinogenesis; cyclin D1; CCND1; retinoblastoma protein; RB1; carcinoma in situ Lung cancer has become a worldwide problem with a greater than tenfold increase in incidence of reported disease since 1930. Chronic exposure to bronchial irritants appears to lead to epithelial changes, scattered throughout the tracheobronchial tree (Auerbach et al, 1962a(Auerbach et al, ,b, 1975. Patients with lung cancer have a much greater frequency of epithelial hyperplasia in main bronchi (>90%) compared with patients (10%) who have never smoked (Auerbach et al, 1961). The best evidence for an association between carcinoma in situ and invasive carcinoma probably comes from sputum cytology from uranium miners, which showed increasingly abnormal epithelial cells as the patients progressed towards invasive lung tumours (Saccomanno et al, 1974). These results suggest that the whole tracheobronchial tree is affected by carcinogen exposure. Cells with genetic lesions resulting in a growth advantage are likely to replace the epithelium of the whole tracheobronchial tree and, in the case of additional genetic events, may show invasive growth (Thibervill...

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“…Overexpression of cyclin D1 releases a cell from its normal control and causes transformation to a malignant phenotype. Previous studies have demonstrated that cyclin D1 is increased in adenomatous polyps and in both sporadic and familial forms of colorectal cancer (Motokura and Arnold, 1993;Bartkova et al, 1994;Arber et al, 1996Arber et al, , 1997. Consistent with these prior observations, in the present study, gastrin increased cyclin D1 levels in vivo and in vitro, an effect that was reversed with NS-398.…”

Section: Discussionmentioning

confidence: 99%

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

et al. 2002

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Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E 2 , the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

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Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis

Cited by 275 publications

References 4 publications

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

Abnormal expression of CCNDI and RBI in resection margin epithelia of lung cancer patients

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

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