Apoptosis and its correlation with proliferative activity in rectal cancer

Kim, Young‐Ho; Lee, Jun Haeng; Chun, Ho-Kyung; Nam, Seok‐Jin; Lee, Woo Yong; Song, Sang Yong; Kwon, Oh-Hyun; Hyun, Jae Chun; Sung, In Kyung; Son, Hee Jung; Rhee, Poong‐Lyul; Kim, Jae J; Paik, Seung Woon; Rhee, Jong Chul; Choi, Kyoo Wan

doi:10.1002/jso.10063

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…In fact, both Watanabe et al [28] and Evertsson et al [29] observed an increase in apoptosis and proliferation activities during the course of tumour progression from early to advanced stages of CRC. The same conclusion was reached in a study of rectal cancer by Kim et al [30]; these researchers also linked apoptosis to lymphatic invasion. Recently, authors that were investigating the relationship between KRAS mutations and prognoses for CRC cases have observed that KRAS mutations lead to the higher turnover of colorectal tumour cells, which stimulates both mitosis and apoptosis and is related to a poor survival of CRC [31].…”

Section: Discussionsupporting

confidence: 73%

The role and prognostic value of apoptosis in colorectal carcinoma

et al. 2013

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BackgroundAlterations to apoptosis are a common occurrence in human tumours. The aim of our study was to determine the influence of apoptotic variations on the carcinogenesis and prognosis of colorectal carcinomas (CRCs).MethodsA TUNEL assay was performed on archival material from 103 colorectal carcinomas, 26 adenomas and 20 samples of normal epithelia.ResultsThe number of apoptotic cells was higher in CRCs (1.09 ± 0.13) than in adenomas (0.38 ± 0.23, p = 0.059) and normal epithelium (0.06 ± 0.04, p = 0.001). In addition, the apoptotic index (AI) was greater in metastatic disease (stage IV) than in other stages (p = 0.017). No relationship was found between apoptotic rates and age, gender or tumour grade. However, patients with tumours that showed higher AI values had a significantly lower disease-free survival (DFS) and overall survival (OS) than those with tumours that had lower AIs (p = 0.020 and p = 0.027). In a multivariate Cox proportional hazards model, AI remained a significant independent predictor of survival.ConclusionsWe conclude that disregulated apoptosis is an important event during CRC development and progression. Higher AIs are associated with more aggressive tumours and a poorer prognosis for patients with CRC.

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Section: Discussionsupporting

confidence: 73%

The role and prognostic value of apoptosis in colorectal carcinoma

et al. 2013

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“…We observed that patients showing both high apoptosis and high proliferation, of which 68 % of the patients corresponded to the “all low” combined marker group, showed the shortest survival. This finding is supported by literature, in which both increased apoptosis and increased proliferation were reported in rectal tumors with lymph node metastases as compared to non-metastatic tumors [50]. The distorted balance between the apoptosis pathways and cellular proliferation in the “all low” combined marker group hence might explain the observed survival data.…”

Section: Discussionsupporting

confidence: 83%

DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence

et al. 2014

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Deregulation of the apoptotic pathway, one of the hallmarks of tumor growth and -progression, has been shown to have prognostic value for tumor recurrence in rectal cancer. In order to develop clinically relevant bio-markers, we studied the methylation status of promoter regions of key apoptosis genes in rectal cancer patients, using methylation-sensitive restriction enzymes. DNA was extracted from fresh-frozen tumor tissues of 49 stage I-III rectal cancer patients and 10 normal rectal tissues. The results of this pilot study were validated in 88 stage III tumor tissues and 18 normal rectal tissues. We found that methylation of the intrinsic apoptotic pathway genes Apaf1, Bcl2 and p53 correlated with the apoptotic status (M30) of the tumor. Combined survival analyses of these three genes, based on the number of genes showing high methylation (all low, 1 high, 2 high or all high), showed shorter patient survival and recurrence-free periods with an increasing number of methylated markers. Multivariate analyses showed significant differences for overall survival (p = 0.01; HR = 0.28 (0.09–0.83)), cancer-specific survival (p = 0.004; HR = 0.13 (0.03–0.67)) and distant recurrence-free survival (p = 0.001; HR = 0.22(0.05–0.94)). The shortest survival was observed for patients showing low methylation of all markers, which—as was expected—correlated with high apoptosis (M30), but also with high proliferation (Ki-67). The study of epigenetic regulation of apoptosis genes provides more insight in the tumorigenic process in rectal cancer and might be helpful in further refining treatment regimens for individual patients.

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“…The interobserver agreement of percentage scores may be better assessed in colorectal adenomas known to frequently overexpress the protein. 23 Our results show that Bcl-2 expression scored as 0% positive tumor cells vs any tumor cell staining leads to the highest degree of interobserver agreement in rectal tumors of the same stage.…”

Section: Discussionmentioning

confidence: 56%

“…This result is in line with the literature which states that the frequency of Bcl-2 expression in rectal carcinoma is less than 30%. 23 Kim et al 23 demonstrated that the rate of Bcl-2 overexpression decreases with more advanced Dukes stage. In this study, 98% of rectal biopsies were taken from patients with clinically diagnosed cT3 tumors.…”

Section: Discussionmentioning

confidence: 99%

Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer

et al. 2006

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Molecular tumor markers are often studied in colorectal cancer using immunohistochemistry to determine their prognostic or predictive value. Protein expression is typically assigned a 'positive' score based on a predetermined cutoff. A semiquantitative scoring method that evaluates the percentage of positive tumor cells (0-100%) may provide a better understanding of the prognostic or predictive significance of these markers. The aim of this study was to assess and compare the interobserver agreement of immunohistochemistry scores using a percentage scoring method and three categorical scoring systems. Immunohistochemistry for p53, Bcl-2, vascular endothelial growth factor (VEGF) and apoptotic protease activating factor-1 (APAF-1) was performed on 87 tumor biopsies from patients with rectal carcinoma and scored independently by four pathologists as the percentage of positive tumor cells. Interobserver agreement was assessed by the intraclass correlation coefficient. The intraclass correlation coefficients for p53 and VEGF (40.6) indicate substantial agreement between observers. The distribution of Bcl-2 and APAF-1 scores in addition to weaker interobserver agreement by percentage scoring suggest that this approach may not be appropriate for these proteins. In conclusion, p53 and VEGF protein expression assessed by immunohistochemistry in colorectal cancer and scored as a percentage of positive tumor cells may be a viable alternative scoring method.

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Apoptosis and its correlation with proliferative activity in rectal cancer

Abstract: Our results suggest that the susceptibility to apoptosis in rectal cancer is clearly related to the proliferative activity and high turnover rate of tumor cells may contribute to lymph node metastasis.

Cited by 13 publications

References 29 publications

The role and prognostic value of apoptosis in colorectal carcinoma

The role and prognostic value of apoptosis in colorectal carcinoma

DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence

Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer

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