Apoptosis in colorectal carcinoma occurring in patients aged 45 years and under: relationship to prognosis, mitosis, and immunohistochemical demonstration of p53, c-myc and bcl-2 protein products

Langlois, Neil E. I.; Lamb, Justin; Eremin, O.; Heys, Steven Darryll

doi:10.1002/(sici)1096-9896(199708)182:4<392::aid-path874>3.0.co;2-g

Cited by 49 publications

(19 citation statements)

References 29 publications

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“…Other studies reported an inverse relationship between apoptosis and survival: a low frequency of apoptosis was shown to predict a shorter survival time, either overall survival or risk of recurrence (Baretton et al, 1996;Bedi et al, 1995;Kawasaki et al, 1998;Langlois et al, 1997;Sugamura et al, 1998;Tsujitani et al, 1996). However, in contrast to our study, in some of these studies, relationships between mutations in p53 or bcl-2 and the presence of apoptosis were reported (Baretton et al, 1996;Langlois et al, 1997;Tsujitani et al, 1996).…”

Section: Discussioncontrasting

confidence: 96%

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

Jonges

Nagelkerke²,

Ensink

et al. 2001

Laboratory Investigation

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SUMMARY:Several techniques to determine apoptotic frequencies in tumors have been described. In this study, we report that biochemical detection of enzymatic caspase-3 activity is a simple and quantitative technique to measure apoptosis in colorectal tumor cells. The relevance of the level of apoptosis in colorectal cancer for the clinical course remains unclear. Therefore, we studied the correlation between caspase-3 activity and prognosis of the disease in relation to different factors known to be involved in apoptosis induction. High caspase-3 activity significantly correlated with a higher risk of recurrence and was preferentially found in tumors of the right side of the colon. No correlation was detected between high caspase-3 activity and altered protein expression of p53, ␤-catenin, or proteins of mismatched repair genes. This indicates that high caspase-3 activity has no evident correlation with the genetic Wnt-signaling or the mismatch repair mutational pathways. The caspase-3 activity significantly correlated with CD57 ϩ tumor infiltrating cells. Therefore, high caspase-3 activity in right-sided tumors might be induced by a specific lymphocytic reaction. (Lab Invest 2001, 81:681-688).A poptosis is an essential biologic process. As well as having a role in controlling cell number during early development, apoptosis is important for the removal of infected or genetically altered cells (Duke et al, 1996). Defects in the apoptotic mechanism are often found in neoplastic growth (Duke et al 1996;Green and Martin, 1995;Tompson, 1995), which is also the case in colorectal cancer (Evertsson et al, 1999;Gryfe et al, 1997;Tsujitani et al, 1996). Development of colorectal cancer proceeds through a series of genetic alterations that result in the activation of oncogenes and loss of tumor suppressor genes (Gryfe et al 1997;Rafter and Glinghammar, 1998;Ilyas et al, 1999). Mutations in genes known to be involved in cell cycle regulation, such as APC, p53, ␤-catenin, deleted in colorectal cancer (DCC), and K-ras, have been reported in colorectal cancer (reviewed in Gryfe et al, 1997). Furthermore, mutated genes involved in DNA mismatch repair can contribute to tumor growth. Alterations in these mismatch repair genes will lead to a microsatellite instability phenotype (MSI) (reviewed in Lothe, 1997). During tumorigenesis one of the target genes that is preferentially inactivated due to MSI is transforming growth factor ␤ receptor II (TGF␤RII) (Markowitz et al, 1995;Akiyama et al, 1996). Inactivation of TGF␤RII on cells down-regulates the suppressive function of TGF␤ on cell proliferation and in that way also results in disturbance of growth control (DeVisser and Kast, 1999). Most of the hereditary nonpolyposis colorectal tumors (HNPCC) exhibit MSI, whereas in sporadic colorectal cancers only 3% to 10% show this phenotype. This low rate of MSI in sporadic colorectal cancers seems to be caused by somatic inactivation of hMLH1 (Lothe, 1997).As well as the occurrence of apoptosis in cells caused by intrinsic factors, apopto...

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Section: Discussioncontrasting

confidence: 96%

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

Jonges

Nagelkerke²,

Ensink

et al. 2001

Laboratory Investigation

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“…Others (2,4,9,14,24) had showed that patients with bcl-2 positive colorectal carcinoma had a more favourable clinical course. Finally, some studies (5,12,16,19,23) had failed to demonstrate any correlation between bcl-2 expression and well-known prognostic features, in agreement with our results.…”

Section: Discussionsupporting

confidence: 92%

“…Technical differences can be expected for settings, antibodies, methods of antigenic retrieval, staining scores and interpretation criteria. Immunoreactivity can range from less than 10% to nearly 100%, depending on the tissue sample and interpretation criteria of the reaction (2,4,6,10,12,16,17,19,24,26) . In this study, 29.5 % of the cases were bcl-2 positive, similar to the results of other authors (6,10,24) , despite differences on the immunohistochemistry method.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 expression in rectal cancer

Contu

Moreira

2006

Arq. Gastroenterol.

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-Background -Proteins involved in apoptosis process seem to play an important role in colorectal carcinogenesis.Aim -To determine the prevalence of bcl-2 protein immunohistochemical expression and its relation with clinical and histopathological variables of rectal adenocarcinoma. Patients and methods -One hundred and thirty-two patients operated at "Hospital de Clínicas de Porto Alegre", Porto Alegre, RS, Brazil, between 1988 and 1999 were studied through immunohistochemical reaction using a monoclonal antibody anti-bcl-2 on formalin-fi xed, paraffi n-embedded tissue samples.Results -The prevalence of bcl-2 protein was 29.5%. There was a signifi cant increased number of positive bcl-2 cases among women as compared to men. There was no signifi cant association between bcl-2 and age, tumour site, histological grade, mucin production, depth of invasion, lymphatic involvement, distant metastasis or stage, despite a trend showing decreased immunoreactivity to bcl-2 among poorly and moderately differentiated tumours, as well as disseminated disease.Conclusions -Analysis of bcl-2 protein expression in tumour tissues, as well as other oncoproteins, may have a role in predict therapeutic response and prognosis of colorectal cancer. However, the potential use of bcl-2 protein assessment in the clinical set for management of rectal cancer remains to be determined.

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“…This might have been partly due to the small number of cases examined, or it might imply the predominance of a p53-independent pathway in the induction of apoptosis in human colorectal carcinomas. Again, AI did not exhibit the expected correlation with bax and bcl-2 protein expression, as was also reported for gastric (Sugamura et al, 1997) and colorectal (Langlois et al, 1997) cancers. However, these findings are in keeping with the hypothesis that in a proportion of colorectal cancer cases the bcl-2 proto-oncogene expression may be downregulated at a post-transcriptional level (Berney et al, 2000) since the expression of bcl-2 protein was gradually and significantly lost during the progression from moderately dysplastic adenoma to primary colorectal carcinoma; conversely, the cellular expression of bcl-2 mRNA gradually increased during the successive steps of carcinogenesis.…”

Section: Discussionsupporting

confidence: 70%

“…A prognostic role of the AI has been postulated for patients with colorectal cancer, underlying an aggressive pattern in presence of a low frequency of apoptotic cells (Langlois et al, 1997;Kawasaki et al, 1998;Sugamura et al, 1998;Tenjo et al, 2000). It was recently demonstrated that preoperative treatment with tegafur (a prodrug of 5-FU) (Matsuura et al, 2000) or 5-FU (Yamane et al, 1999) enhances apoptosis in human colorectal carcinoma, and that an increase in the apoptotic index after short-term cytostatic treatment is associated with objective responses in patients with rectal cancer (Farczadi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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SummaryThe clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short-and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.

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Apoptosis in colorectal carcinoma occurring in patients aged 45 years and under: relationship to prognosis, mitosis, and immunohistochemical demonstration of p53, c-myc and bcl-2 protein products

Cited by 49 publications

References 29 publications

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

Bcl-2 expression in rectal cancer

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

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