Nonsteroidal anti-inflammatory drugs, apoptosis, and colorectal adenomas

Martin, Christopher; Connelly, Alexandra E.; Keku, Temitope O.; Mountcastle, Sally B.; Galanko, Joseph; Woosley, John T.; Schliebe, Barbara; Lund, P. Kay; Sandler, Robert S.

doi:10.1053/gast.2002.37053

Cited by 78 publications

(75 citation statements)

References 17 publications

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“…37,38 Another study looking at rectal biopsies of patients with colorectal adenomas found that high levels of apoptosis correlated with lower incidence of adenomas. 39 We examined apoptosis by means of an ELISA that measures the content of cytoplasmic nucleosomes, a defining feature of apoptosis. We found significantly decreased apoptosis in mucosal homogenates from Apc Min/1 mice compared to both wild-type and Apc Min/1 ; Gucy2c 2/2 mucosa.…”

Section: Discussionmentioning

confidence: 99%

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Mann

Steinbrecher

Stroup

et al. 2005

Intl Journal of Cancer

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Guanylyl cyclase C (GC-C), a transmembrane receptor for bacterial heat-stable enterotoxin and the mammalian peptides guanylin and uroguanylin, mediates intestinal ion secretion and affects intestinal cell growth via cyclic GMP signaling. In intestinal tumors, GC-C expression is maintained while guanylin and uroguanylin expression is lost, suggesting a role for GC-C activation in tumor formation or growth. We show by in situ hybridization that GC-C expression is retained in adenomas from multiple intestinal neoplasia (Apc Min/+ ) mice. In order to determine the in vivo role of GC-C in intestinal tumorigenesis, we generated Apc Min/+ mice homozygous for a targeted deletion of the gene encoding GC-C and hypothesized that these mice would have increased tumor multiplicity and size compared to wild-type Apc Min/+ mice on the same genetic background. In contrast, the absence of GC-C resulted in a reduction of median polyp number by 55%. There was no change in the median diameter of polyps, suggesting no effect on tumor growth. Somatic loss of the wild-type Apc allele, an initiating event in intestinal tumorigenesis, also occurred in polyps from GC-C-deficient Apc Min/+ mice. We have found increased levels of apoptosis as well as increased caspase-3 and caspase-7 gene expression in the intestines of GC-C-deficient Apc Min/+ mice compared with Apc Min/+ mice. We propose that these alterations are a possible compensatory mechanism by which loss of GC-C signaling also affects tumorigenesis. Published 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Mann

Steinbrecher

Stroup

et al. 2005

Intl Journal of Cancer

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“…However, it has been noted that the two sulindac metabolites do have differential effects on apoptosis of SW480 human CRC cells (Piazza et al, 1997b). Recently, it has been reported that human colorectal mucosal apoptosis rates are not increased in NSAID users (Martin et al, 2002). This suggests that any proapoptotic effect of NSAIDs may also play only a minor role in their chemopreventative activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Effect of nonsteroidal anti-inflammatory drugs on β-catenin protein levels and catenin-related transcription in human colorectal cancer cells

2004

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Elevated b-catenin levels in human colorectal cancer (CRC) cells lead to increased trans-activation of 'protumorigenic' b-catenin/Tcell factor (TCF) target genes such as cyclin D1. Therefore, possible targets for the anti-CRC activity of nonsteroidal anti-inflammatory drugs (NSAIDs) are b-catenin and catenin-related transcription (CRT). We tested the antiproliferative activity and the effects on levels of b-catenin and cyclin D1 protein, as well as CRT (measured using a synthetic b-catenin/TCF-reporter gene [TOPflash]), of a panel of NSAIDs (indomethacin, diclofenac, sulindac sulphide and sulphone, rofecoxib; range 10 -600 mM) on SW480 human CRC cells in vitro. Following NSAID treatment, there was no consistent relationship between reduced cell proliferation, induction of apoptosis and changes in b-catenin protein levels or CRT. All the NSAIDs, except rofecoxib, decreased nuclear b-catenin content and cyclin D1 protein levels in parallel with their antiproliferative activity. However, cyclin D1 downregulation occurred prior to a decrease in total b-catenin protein levels and there was no correlation with changes in CRT, suggesting the existence of CRT-independent effects of NSAIDs on cyclin D1 expression. In summary, NSAIDs have differential effects on b-catenin protein and CRT, which are unlikely to fully explain their effects on cyclin D1 and their antiproliferative activity on human CRC cells in vitro.

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“…There seems to be no correlation between the proliferation index in normal mucosa and the capacity of predicting a neoplastic lesion in the future [6,8]. When considering apoptosis, this is known to be significantly less in the normal mucosa of patients with adenoma than in controls [9,10], and the proapoptotic response induced by biliary acids in the normal mucosa is significantly smaller in patients with a history of CRC than in individuals who are neoplasia free [11]. These data about cellular kinetics in normal mucosa should be interpreted cautiously because we have to consider that supposedly "normal" mucosa is, in reality, a heterogeneous entity.…”

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Aberrant crypt foci: endoscopic assessment and cell kinetics characterization

Figueiredo

Donato

Urbano

et al. 2008

Int J Colorectal Dis

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Background and aims Aberrant crypt foci (ACF) are preneoplastic lesions in animal models of colorectal cancer. The aim of the study is to investigate if ACF are involved in human colorectal carcinogenic process and if they can be helpful in predicting the presence of a colorectal neoplasia. Methods The study included, between 2003 and 2005, 182 patients, 62 with adenoma, 55 with colorectal carcinoma, 53 without colorectal lesions, and 12 with nonneoplastic mucosal polyps. The number of rectal ACF was determined by colonoscopy. Proliferation and apoptosis indexes were evaluated by immunohistochemistry in rectal ACF, in normal rectal mucosa, and in carcinomatous tissue. Results The mean number of rectal ACF in patients with rectal neoplasia was 12.64, significantly higher than in patients with neoplastic lesions elsewhere in the colon (p= 0.01). The apoptosis index in ACF of patients with colorectal carcinoma or adenoma aged 50 years or older was significantly lower than in younger patients (1.3% vs 2.7%, p=0.01) and, in patients with carcinoma, lower than in normal mucosa (1.1% vs 2.1%, p=0.002). The proliferation index was significantly higher in ACF of patients with colorectal neoplasia aged less than 50 years than in normal mucosa (10.9% vs 7.7%, p=0.02). The apoptosis index in ACF foci of patients with carcinoma (1.1%) was significantly lower than in patients without lesions (2.2%) and than in normal mucosa (2%). The mean number of ACF is significantly higher in patients with polyps larger than 1 cm (11.28 vs 6.27, p=0.02). Conclusion Aberrant crypt foci probably precede the appearance of neoplasia and may be helpful in predicting the presence of a colorectal neoplastic lesion.

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Nonsteroidal anti-inflammatory drugs, apoptosis, and colorectal adenomas

Abstract: Our observations suggest that NSAID use and higher levels of mucosal apoptosis are independently associated with a lower prevalence of adenomas. The study shows a strong field effect for apoptosis.

Cited by 78 publications

References 17 publications

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Effect of nonsteroidal anti-inflammatory drugs on β-catenin protein levels and catenin-related transcription in human colorectal cancer cells

Aberrant crypt foci: endoscopic assessment and cell kinetics characterization

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