Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: A tissue microarray study of 460 patients

Watson, Nicholas; Madjd, Zahra; Scrimegour, Duncan; Spendlove, Ian; Ellis, Ian O.; Scholefield, J H; Durrant, Lindy G.

doi:10.1186/1477-7819-3-47

Cited by 36 publications

(15 citation statements)

References 26 publications

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“…Expression of Bcl2 and p53 have previously been reported (Watson et al , 2005). As a marker of IFN- γ -induced activation, expression of MHC-II on tumour cells and stroma-associated cells was measured.…”

Section: Resultsmentioning

confidence: 81%

“…The study population comprised a series of 462 consecutive patients undergoing elective surgical resection of a histologically proven sporadic primary colorectal cancer at the University Hospital, Nottingham, UK (Table 1; Durrant et al , 2003; Watson et al , 2005; Watson et al , 2006a; Duncan et al , 2007; Ullenhag et al , 2007; McGilvray et al , 2009; Simpson et al , 2010). These patients were treated between 1 January 1994 and 31 December 2000; this time period allowed meaningful assessment of the prognostic markers studied.…”

Section: Methodsmentioning

confidence: 99%

“…(O'Connell et al , 2000; Mild et al , 2002; Mazelin et al , 2004; Watson et al , 2005; Dyer et al , 2007; Ullenhag et al , 2007; Krajewska et al , 2008; Hector and Prehn, 2009; Yang et al , 2009). The interplay between the tumour and its associated stroma is complex.…”

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confidence: 99%

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High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival

et al. 2013

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Aim:The primary aim was to determine the prognostic significance of apoptosis in colorectal tumour cells and tumour-associated stroma. A secondary aim was to determine whether apoptosis was related to immune surveillance.Methods:Immunohistochemistry was performed using monoclonal antibodies recognising cleaved caspase-3 (CC3), cleaved poly (ADP-ribose) polymerase (PARP), p53, Bcl2, MHC-II, B cells (CD16), macrophages (CD68) and T cells (CD3), on a tissue microarray of 462 colorectal tumours.Results:Kaplan–Meier analysis demonstrated that patients with high expression of CC3 in the tumour or CC3 or cleaved PARP in tumour-associated stroma have a good prognosis. This suggests that tumour stroma is promoting tumourigenesis and that high levels of death within the stroma breaks this link. CC3 levels in the tumour correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. CC3 levels on tumour-associated stroma also correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. Tumour cells express MHC-II in response to IFN-γ, suggesting that this may be one of the initiators of apoptosis within the good prognosis tumours. Although 73% of the MHC-II-positive tumour had high levels of apoptosis, many tumours had high levels of apoptosis in the absence of MHC-II, implying that this is only one of many causes of apoptosis within tumours. On multivariate analysis, using Cox's proportional hazards model, tumour stage, vascular invasion and expression of CC3 in tumour-associated stroma were shown to be independent markers of prognosis.Conclusion:This study shows that a high level of apoptosis within colorectal tumour-associated stroma is an independent marker of good prognosis.

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Section: Resultsmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

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High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival

et al. 2013

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“…In contrast, Baretton et al(1996) reported a poor clinical outcome of patients with non-metastatic colorectal tumors that did not express bcl-2 but showed nuclear accumulation of p53. Watson et al(2005) reported patient stratification by combined p53/bcl-2 phenotype provides stage-independent prognostic information in colorectal cancer. Specifically, that up to a quarter of patients showed a good prognosis p53(−)/bcl-2(+) phenotype.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of bcl-2 and p53 expression in colorectal carcinoma

Zhao

Ding

Peng

et al. 2005

J. Zhejiang Univ. - Sci. B

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Abstract:Objective: This study was designed to detect the expression of bcl-2 and p53 proteins in colorectal carcinomas and to determine their association with the patient survival and stage of the diseases. Methods: Immunohistochemistry method was used to detect the expression of bcl-2 and p53 proteins in 93 cases of colorectal carcinoma. The stain results were obtained by analyzing the clinic-pathological characteristics of patients. Results: Fifty-seven percent (53/93) of the colorectal carcinomas were bcl-2 protein positive. The positive rate of bcl-2 protein in lymph node involvement cases was lower (15/37) than the cases without node involvement (38/58, P<0.01). The positive rate of p53 protein was 43% (40/93) in colon-rectum carcinomas. No significant correlation was observed between p53 protein expression and clinic-pathological manifestations (P>0.05) but the survival was significantly worse (P=0.0001) in the p53 protein positive cases. Neither bcl-2 nor p53 alone was correlated with stage of the disease. When combined bcl-2/p53 status was analyzed, a group with bcl-2(+) and p53(−) had the best prognosis. This group was significantly associated with earlier Dukes' stages (P=0.1763). In multivariate Cox regression analysis, lymph node involvement and p53 protein expression were two independent factors correlated with survival time. Conclusion: The expression of bcl-2 and p53 represent biological characteristics of colorectal carcinomas. Assessment of both bcl-2 and p53 status may be valuable in predicting the prognosis of patients.

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“…The colorectal tumour array, produced in house and previously described, was used to analyse tumour binding [33], [34], [35], [36]. Immunohistochemical analysis of 692/29, BR96 and 2-25 LE binding on both arrays was performed using a routine streptavidin-biotin peroxidase method.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Targeting of Lewisy and Lewisb with a Novel Monoclonal Antibody 692/29

Noble

Spendlove²,

Harding³

et al. 2013

PLoS ONE

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BackgroundSeveral monoclonal antibodies (mAbs) recognising Lewisy, such as BR96, have reached the clinic but have failed to show good anti-tumour responses with an acceptable level of toxicity. No Lewisb mAbs have been trialled in patients. In this study we compare the specificity of three mAbs; BR96 (Lewisy), 2-25 LE (Lewisb) and 692/29 that recognises a unique facet of both Lewisy and Lewisb. We then assessed the in vivo therapeutic effect of 692/29 using xenograft models.Methodology/Principal FindingsUsing a glycan array, each mAb was shown to display a different binding pattern with only 692/29 binding to both Lewisy and Lewisb. 692/29 was able to kill tumour cells over-expressing Lewisy/b directly, as well as by antibody and complement mediated cytotoxicity (ADCC/CDC), but failed to kill cells expressing low levels of these haptens. In contrast, BR96, directly killed cells expressing either high or low levels of Lewisy perhaps explaining its toxicity in patients. 2-25 LE failed to cause any direct killing but did mediate ADCC/CDC. Both 692/29 and BR96 bound to >80% of a panel of over 400 colorectal tumours whereas 2-25 LE showed lower reactivity (52%). 692/29 demonstrated more restricted normal tissue reactivity than both BR96 and 2-25 LE. 692/29 anti-Lewisy/b mAb also showed good in vivo killing in xenograft models.Conclusions/SignificanceMAbs targeting both Lewisy and Lewisb may have a therapeutic advantage over mAbs targeting just one hapten. 692/29 has a more restricted normal tissue distribution and a higher antigen threshold for killing which should reduce its toxicity compared to a Lewisy specific mAb. 692/29 has an ability to directly kill tumours whereas the anti-Lewisb mAb does not. This suggests that Lewisy but not Lewisb are functional glycans. 692/29 showed good anti-tumour responses in vivo and is a strong therapeutic candidate.

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Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: A tissue microarray study of 460 patients

Cited by 36 publications

References 26 publications

High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival

High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival

Prognostic significance of bcl-2 and p53 expression in colorectal carcinoma

Therapeutic Targeting of Lewisy and Lewisb with a Novel Monoclonal Antibody 692/29

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