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298Cyclin A and Cyclin D1 as Significant Prognostic MarkersDISCUSSIONThe proliferative activity of colorectal cancercells has been investigated in several studieseither by immunohistochemical determinationof cell proliferation index using antibodies tosome types of cyclins or by flow cytometricdetermination of the S phase fraction of the cellcycle [11].Although Leach et al. [20] did not find cyclinDI gene amplification in a panel of 47 CRC celllines, its protein was overexpressed in about30% of colon carcinoma cases that were includedin the studies of Bartakova et al. [2] and Arberet al. [1]. In the former study, the authors statedthat cyclin D1is aberrantly accumulated in asignificant subset of human CRC cases and thatthe cell lines derived from colon cancer aredependent on this cyclin protein in their cellcycle progression. Moreover, Arber et al. [1]demonstrated that overexpression of cyclin DIwas detected in about 30% of adenomatouspolyps of the colon indicating that this overexpressionis a relatively early event in coloncarcinogenesis that could possibly be responsiblefor the occurrence of pathological changes inthe mucosa that precedes neoplastic transformation.More recently, Holland et al. [13], Pasz-Walczak et al. [27] and Utsonomiya et al.[34]reported up-regulation of cyclin D1 in 58.7%,100% and 43% of their studied cases, respectively,using IHC techniques and/or westernblotting.In the present study, up-regulation of cyclinDI was detected in 68% of the studied cases.Cyclin D1SI was significantly higher in carcinomasthan in normal colorectal mucosa, and inpoorly-differentiated adenocarcinomas it wasapproximately twice that of other histologicaltypes. Amplification and/or overexpression ofcyclin D1 correlated well with deeply invasivetumors and positive lymph node metastasis. Ourresults in this regards are consistent with mostof the available reports in this context [11,21]. In2001, Holland et al., [13] studied 126 cases ofCRC and demonstrated that deregulation ofcyclin D1 and p21WAF proteins are importantin colorectal tumorigenesis and have implicationsfor patient prognosis. Similarly, McKay et al.[23] studied some cell cycle-checkpoint proteinsincluding cyclin D1, p53, p16, Rb-1, PCNA andp27 in CRC. They found that cyclin D1 was theonly protein examined that was related to improvedoutcome in these patients. In addition toour present work, the results of these previouslymentioned studies lead us to assume that cyclinD1 is a valuable prognostic marker in CRCpatients. However, few studies failed to detectany correlation between cyclin DI overexpressionand the clinicopathological factors in CRC [1,2].The controversy in the results of different studiescould partially be explained by the difference inthe sampling of studied cases. The present studyincluded 24 cases of poorly differentiated adenocarcinoma,which was not common in otherstudies of colorectal carcinoma in western countries.This was possible because unlike CRC ofthe western countries, which is usually of lowhistological grade, the majority of CRC casesdiagnosed in Egypt are of high histological grade[32]. However, our results are consistent withthose of Handa et al. [11] since they were ableto include an appreciably large number of poorlydifferentiatedadenocarcinoma cases in theirstudy. The correlation between cyclin D1 overexpressionand the high histological grade wasalso reported in other tumor types. In non-smallcell lung carcinomas, cyclin DI immunostainingwas prominent in poorly differentiated areas butabsent in the well-differentiated ones [22]. Inaddition, PRAD-1/cyclin DI gene amplificationand overexpression of its mRNA have beenfound in squamous cell carcinomas of the larynxin association with invasive, high grade tumorswith positive lymph node metastasis [15]. Anotherpossible explanation for the observed controversyin the results obtained from different studies isthe difference in the detection method used sinceIHC, western blotting, Southern blotting; northernblotting and flowcytometry were all usedfor studying cyclins.In the present work, overexpression of cyclinD1 was detected in a higher percentage thanamplification of the PRAD-1/cyclin DI genewith a 63.6% concordance. This was similarlyreported by Bartakova et al. [2] who mentionedthat although immunohistochemical detectionof cyclin D1distinguishes tumors with the 11q13amplification (The PRAD-1/cyclin DI gene locus)from non-amplified cases, it also appearsto identify a subset of cases in which cyclin D1is overexpressed in the absence of gene amplification.Consistent with this hypothesis arereports of elevated cyclin D1 mRNA levels [3]and immunohistochemically detectable accumulationof the protein [8] in over one-third of breast
Abeer A. Bahnassy, et al. 299cancer cases at a frequency significantly higherthan that deduced from DNA amplification studies.These data imply that mechanisms otherthan gene amplification can also lead to deregulationand accumulation of cyclin D1 in commonsolid tumors.So far, studies have been done to reveal theprognostic significance of cyclin DI overexpressionin various carcinomas, including CRC [21].However, the studies yielded conflicting results.This may indicate that organ heterogeneity playsa role in the involvement of cyclin DI in thedevelopment and progression of cancer. In ourstudy, patients with tumors that exhibited cyclinDI overexpression tended to have poor prognosis.It is well known that cyclin A is involved inthe onset of DNA replication [9] and is requiredfor G2-M transition in mammalian cells [26].Overexpression of cyclin A would, therefore,contribute to the high proliferative activity incancer cells. Cyclin A achieves its maximal levellate in the cycle (S to G2 phase) leading to directentry of cancer cells into mitosis and may, thus,reflect the high proliferative activity of cancercells more sharply than Ki- 67. It was reportedthat 75% of non-small cell lung carcinoma patientsexhibited immunohistochemical stainingfor cyclin A and that patients with cyclin Apositive carcinomas had significantly shortermedian survival times [35]. In addition, Chao etal. [4] found that 39% of patients with humanhepatoecellular carcinoma exhibited cyclin Aoverexpression in tumorous tissue by westernblot analysis. They mentioned that overexpressionof cyclin A could be an independent prognosticfactor in hepatocellular carcinoma. Incontrast, Wang et al. [36] reported that cyclin Aexpression in normal colon mucosa was higherthan that in cancer tissue in 63 % of their studiedcases, and only 10 % of the carcinomas hadhigher cylcin A expression. However, Handa etal. [11] were able to detect cyclin A overexpressionin 77% of their 73 cases of CRC. They alsodemonstrated that cylcin A could be used as aprognostic factor of CRC. More recently, Hebermannet al. [12] studied cases of ulcerative colitiswith and without an associated adenocarcinomafor the presence of cyclin A overexpression.They found that cyclin A overexpression washigher in cases of ulcerative colitis with adenocarcinomasthan those without adenocarcinomas.Consequently, they concluded that cyclin A couldbe used for monitoring ulcerative colitis patientsand for the early detection of an emerging carcinomain this high risk group of patients.In our study, cyclin A was detected in 80%of the patients and Cox regression analysisshowed that in addition to cyclin D1, cyclin Acould be used as a prognostic marker in colorectalcarcinoma cases. Our results regarding the prognosticvalue of cyclin A were in agreement withthose of Handa et al. [11].It is difficult to determine the exact reasonfor the controversy in results between the presentwork or the study of Handa et al. [11] and Wanget al. [36]. However, this controversy in resultscould be partially attributed to the inclusion ofa larger number of high-grade tumors in thepresent study and that of Handa et al.[11] or tothe sensitivity of the detection method [36].It would have been useful if we assessed theexpression level of cyclin A by another technique(DNA amplification). This would have addedmore information regarding the gene status onone hand and confirmed the results of IHC onthe other. Unfortunately, this was not possiblebecause in most of the cases included in thepresent work, the extracted DNA was not sufficientto study cyclin A amplification after theassessment of cyclin D1.Nagao et al. [25] reported that histone H3labeling index significantly correlated with ki-67 immunostaining and was high in poorly differentiatedhuman hepatocellular carcinoma. Inour study, histone H3 SI significantly correlatedwith the SI of Ki–67. However, no statisticallysignificant correlation was found between histoneH3 SI and any of the studied clinicopathologicalfactors, although it was higher in adenocarcinomasthan in normal mucosa.Although Ki-67 immunostaining reflects theproliferative activity of CRC, it has not beenrecognized as a significant prognostic factor inthis type of tumors [7,19,29]. However, Suzuki atal. [33] reported that the Ki-67 labeling indexcorrelated with local invasion of colorectal carcinomabut not with the metastatic potential. Inthe present study, there was a significant relationshipbetween the SI of Ki-67 and the degreeof differentiation of the tumors as well as theirsize. However, Kaplan-Meier survival curvesshowed no significant difference in survival rates
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