Proliferation and differentiation of normal and neoplastic cells in the colon of man

Lipkin, Martin

doi:10.1002/1097-0142(197107)28:1<38::aid-cncr2820280108>3.0.co;2-w

Cited by 32 publications

(6 citation statements)

References 4 publications

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“…Tritiated thymidine labeling studies further suggest that their proliferation rate is about 1.5-fold lower than that of normal colon stem cells (47). The lower proliferation rate can be attributed to DNA replication stress-induced senescence (13,14).…”

Section: Nikolaev Et Al Cancer Res; 72(23) December 1 2012mentioning

confidence: 99%

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

et al. 2012

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Oncogene-induced DNA replication stress is thought to drive genomic instability in cancer. In particular, replication stress can explain the high prevalence of focal genomic deletions mapping within very large genes in human tumors. However, the origin of single-nucleotide substitutions (SNS) in nonfamilial cancers is strongly debated. Some argue that cancers have a mutator phenotype, whereas others argue that the normal DNA replication error rates are sufficient to explain the number of observed SNSs. Here, we sequenced the exomes of 24, mostly precancerous, colon polyps. Analysis of the sequences revealed mutations in the APC, CTNNB1, and BRAF genes as the presumptive cancer-initiating events and many passenger SNSs. We used the number of SNSs in the various lesions to calculate mutation rates for normal colon and adenomas and found that colon adenomas exhibit a mutator phenotype. Interestingly, the SNSs in the adenomas mapped more often than expected within very large genes, where focal deletions in response to DNA replication stress also map. We propose that single-stranded DNA generated in response to oncogene-induced replication stress compromises the repair of deaminated cytosines and other damaged bases, leading to the observed SNS mutator phenotype. Cancer Res; 72(23); 6279-89. Ó2012 AACR.

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Section: Nikolaev Et Al Cancer Res; 72(23) December 1 2012mentioning

confidence: 99%

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

et al. 2012

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“…Colonic carcinogenesis is characterized by the progressive loss of homeostatic regulators (Lipkin, 1971;Moss et al, 1996;Shanmugathasan and Jothy, 2000). Alterations in several PKC isoforms occur during colonic malignant transformation, including loss of PKC-d in neoplastic progression (Weinstein, 1991;DeRubertis, 1992, 1994;Davidson et al, 1994;Kahl-Rainer et al, 1994McGarrity and Peiffer, 1994;Wali et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

et al. 2006

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PKC-d is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-d slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-d dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-d using a Zn 2 þ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-d caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, Po0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21 Waf1, a cyclin-dependent kinase (cdk) inhibitor in PKC-d transfectants compared with empty vector (EV) transfected cells, whereas the PKC-d specific inhibitor rottlerin (3 lM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21Waf1 expression. Concomitantly, compared to EV control cells, PKC-d upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-d increased binding of cdk inhibitor p27Kip1 to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-d plays in cell growth and cell cycle regulation, we knocked down PKC-d using specific siRNA oligonucleotides. PKC-d specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKCd protein by more than 80% in Caco-2 cells. Moreover, PKC-d knockdown enhanced cell proliferation (B1.4-2-fold, Po0.05) and concomitantly increased cyclin D1 and cyclin E expression (B1.7-fold, Po0.05). This was a specific effect, as nontargeted PKC-f was not changed by PKC-d siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-d transfectants, compared to EV cells, PKC-d upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-d specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-d regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-d that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-d in colonic carcinogenesis.

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“…To characterize human colorectal tumors, numerous studies have been focused upon enzyme activities (Ahmed et al, 1982;Ahmed, 1984;Denton et al, 1982;Finan et al, 1984;Lipkin, 1977;Weber et al, 1978Weber et al, , 1980Weber et al, , 1981Wolberg and Morin, 1981). These investigations concerned, in particular, the pyrimidine nucleotide pathway, since 5-fluorouracil remains the most effective single therapeutic agent in these tumors.…”

mentioning

confidence: 99%

Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Luccioni

Beaumatin

Bardot

et al. 1994

Intl Journal of Cancer

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The activities of 5 enzymes involved in the pyrimidine metabolism were measured in xenografts of 8 human colon adenocarcinomas and in the corresponding primary tumors and normal tissues. The enzymes studied were thymidine kinase, thymidine phosphorylase, uridine kinase, uridine phosphorylase and thymidylate synthase. With the exception of the phosphorylases in one tumor, all enzyme activities were higher in primary tumors than in the corresponding normal tissues. The average activities of thymidine kinase and thymidylate synthase were of the same order of magnitude in xenografts and in primary tumors. The uridine metabolizing enzymes tend to have a higher activity in xenografts than in primary tumors. The most consistent and significant change was a sharp decrease in thymidine phosphorylase activity in xenografts as compared to primary tumors. Whether or not the difference in thymidine phosphorylase activity between xenografts and primary tumors is related to the contribution of non-cancerous cells in primary tumors remains to be determined. However, these results raise questions concerning the representativeness of xenografts with reference to primary tumors and suggest that care should be taken in the application of this model.

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Proliferation and differentiation of normal and neoplastic cells in the colon of man

Cited by 32 publications

References 4 publications

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

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