Intraepithelial bodies in colorectal adenomas

Rubio, Carlos A.; Alm, Thor; Aly, Andreas; Poppen, B

doi:10.1007/bf02050206

Cited by 16 publications

(12 citation statements)

References 3 publications

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“…15 This specific mutation was also associated with generation of DNA aneuploid subclones. 15 That abnormal mitoses are massively present in human colorectal adenomas 40 and that there is a relatively high incidence of K-ras2 transversions in these lesions 19 -23 also constitute indirect evidence of a link of the two variables.…”

Section: Discussionmentioning

confidence: 99%

Specific K-ras2 Mutations in Human Sporadic Colorectal Adenomas Are Associated with DNA Near-Diploid Aneuploidy and Inhibition of Proliferation

Giaretti

Rapallo

Geido

et al. 1998

The American Journal of Pathology

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Recent studies indicate that p21ras proteins mediate their multiple cell functions through interactions with multiple effectors and that the number of new effectors is growing. We recently reported that K-ras2 mutations in human colorectal adenomas were associated with chromosome instability and proliferation changes. In the present study , we extend these previous observations. Hereditary and multiple (n > 5) adenomas and adenomas with early cancer were excluded. Dysplasia was moderate in 91 cases and high in 25, and the median adenoma size was 1.5 cm. K-ras2 spectrum analysis was done by sequence-specific oligonucleotide hybridization using nuclear suspensions provided by analysis and sorting of multiparameter flow cytometry. In particular , tissue inflammatory cells were separated for DNA diploid tumors, whereas DNA aneuploid epithelial subclones were analyzed separately. K-ras2 mutations and DNA aneuploidy were both detected in 29 of 116 (25%) cases. DNA aneuploid index was in the near-diploid region in the majority of cases. DNA aneuploidy was strongly associated with G3 C/T transversions. An association was also found between low S-phase values and G3 A transitions. These findings were confirmed using multivariate logistic regression analysis to account for the effects of size , dysplasia , site , type , age, and sex. These data suggest that specific K-ras2 mutations in a subgroup of human sporadic colorectal adenomas play a role in chromosome instability and, contrary to expectations , are associated with inhibition of proliferation. (Am J Pathol 1998, 153:1201-1209)Ras proteins participate at the plasma membrane level in transduction of diverse extracellular physiological signals that are thought to induce appropriate gene expression toward proliferation and differentiation. Ras proteins possess an intrinsic GTPase activity and alternate between activated and inactivated forms. The best-known Ras transduction mechanism is a pathway from receptor tyrosine kinases to transcription factors phosphorylated by mitogen-activated protein kinases. Mutations of the ras oncogenes result in constitutive signaling to downstream elements and are detected at high frequency in many types of human cancer.

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Section: Discussionmentioning

confidence: 99%

Specific K-ras2 Mutations in Human Sporadic Colorectal Adenomas Are Associated with DNA Near-Diploid Aneuploidy and Inhibition of Proliferation

Giaretti

Rapallo

Geido

et al. 1998

The American Journal of Pathology

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“…Normal mitotic figures (NMFs) were classified according to the definitions given by Rubio [13]. AMFs were defined as mitoses without the typical aspect of normal mitoses.…”

Section: Examination Of Mitosesmentioning

confidence: 99%

Atypical mitotic figures and the mitotic index in cervical intraepithelial neoplasia

Leeuwen¹,

Pieters²,

Hollema³

et al. 1995

Vichows Archiv A Pathol Anat

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We surveyed cervical intraepithelial neoplasia (CIN) to quantify the proliferation rate and the presence of normal and atypical mitotic figures. In the cervical tissue specimens of 127 women with CIN, the area with the highest cell proliferation was identified and, at that site, the proliferation rate was assessed by calculating the mitotic index (MI). Lesions with an MI < 2 were not considered further. In the area with the highest proliferation rate, 228 mitoses were classified into one of the following groups: normal mitotic figures (NMFs), lag-type mitoses (OLTMs) comprising three group metaphases (3GMs), two group metaphases (2GMs) and other lag-type mitoses (LTMs), multipolar mitoses (MPMs) comprising tripolar mitoses (3PMs) and quadripolar mitoses (4PMs), and other atypical mitotic figures (OAMFs). The median value of the MI increased significantly from 3 in CIN I through 4 in CIN II to 9 in CIN III (P < 0.001). The occurrence of the different LTMs was mutually correlated. The frequency of LTMs increased significantly with increasing CIN grade (P < 0.001), whereas the frequency of NMFs decreased significantly with increasing CIN grade (P < 0.001). The frequency of OAMFs was not related to CIN grade (P = 0.94). MPMs were present in low numbers in a minority of the lesions. Spearman's rank correlation coefficient (with 95% confidence limits) between the MI and the number of LTMs, OAMFs and NMFs was 0.66 (0.53; 0.75), -0.14 (-0.32; 0.05) and -0.51 (-0.63; -0.35), respectively. Increasing CIN grade is associated with increasing MI, increasing numbers of LTMs, and decreasing numbers of NMFs. MPMs are very rare events in CIN. The abundant presence of OAMFs seems to be independent of CIN grade and MI.

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“…Mutations of the ras oncogene have been widely investigated in human colorectal adenomas and carcinomas, one of the most potentially informative systems for studying human tumor progression, and shown to consist mainly of single-base substitutions of the Kirsten-ras oncogene (K-ras) in codons 12 and 13 (Bos et al, 1987;Fearon and Vogelstein, 1990; Vogelstein et al, 1988 Vogelstein et al, , 1989. It is interesting to observe that the frequency of K-ras mutations in human colorectal adenomas is approximately 50%, and that these early preneoplastic tumor lesions are also characterized by frequent atypical mitoses (Rubio, 1991) and DNA aneuploidy (Giaretti and Santi, 1990;Giaretti, 1994;Van den Ingh et al, 1985). In particular, a link appears to exist between K-ras mutations and DNA near-diploid aneuploidy (Giaretti et al, 1995(Giaretti et al, , 1996.…”

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confidence: 94%

Transfection of human mutated K-ras in mouse NIH-3T3 cells is associated with increased cloning efficiency and DNA aneuploidization

et al. 1996

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The aim of the study was to test the hypothesis that a human mutated K-ras protein induces abnormalities in mitosis and development of sub-clones characterized by changes in DNA ploidy and proliferation. For this purpose, we used control and NIH-3T3 mouse cells transfected with the human codon 12 G-C-mutated K-ras oncogene. We found that abnormal mitoses, mainly characterized by lagging chromosomes in prometaphase or anaphase, had a significantly higher frequency in transfected cells than in control cells. The generation of sub-clones was screened by limiting-dilution experiments followed by cell expansion. Cloning efficiency was much higher for the K-ras transfected cells with 858/2112 (41%) successful sub-clones than for control, which provided 564/2592 (22%) sub-clones. DNA flow cytometry of 4.6-diamidino-2-phenilindole-2-hydrochloride-stained nuclei from randomly selected sub-clones was performed in order to evaluate DNA index and S-phase fraction values. We found 9 out of 100 DNA aneuploid sub-clones generated by the K-ras-transfected cells vs. 1 out of 100 for the controls. Overall, our data indicate that high expression of the mutationally activated human K-ras product in NIH-3T3 cells was associated with abnormal mitoses, increase of cloning efficiency and DNA aneuploidization.

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Intraepithelial bodies in colorectal adenomas

Cited by 16 publications

References 3 publications

Specific K-ras2 Mutations in Human Sporadic Colorectal Adenomas Are Associated with DNA Near-Diploid Aneuploidy and Inhibition of Proliferation

Specific K-ras2 Mutations in Human Sporadic Colorectal Adenomas Are Associated with DNA Near-Diploid Aneuploidy and Inhibition of Proliferation

Atypical mitotic figures and the mitotic index in cervical intraepithelial neoplasia

Transfection of human mutated K-ras in mouse NIH-3T3 cells is associated with increased cloning efficiency and DNA aneuploidization

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