Nuclear or cytoplasmic expression of survivin: What is the significance?

Abstract

Growing evidence suggests that survivin expression in cancer cell nuclei may represent an important prognostic marker to predict disease outcome for cancer patients. Current reports in this research area, however, are inconsistent and propose opposing conclusions regarding the significance and prognostic value of survivin nuclear expression. The aim of our study is to review and discuss the data reported in the original publications. We have also provided new experimental data to support our view regarding the possible reasons for the observed inconsistencies in the literature. This would alert researchers to pay attention to potential pitfalls in the determination of nuclear or cytoplasmic expression of survivin for the future. © 2004 Wiley-Liss, Inc. Key words: survivin expression; cancer; cytoplasmic; nuclear; immunohistochemistry; prognostic marker Among the 19 publications relevant to survivin localization in nuclei or cytoplasm in various cancer tissues, 9 showed that the expression of survivin in cancer cell nuclei is an unfavorable prognostic marker, 1-10 whereas studies from 5 of 19 proposed an opposing notion that the nuclear expression of survivin represented a favorable prognostic marker. 10 -14 The remaining 5 publications did not focus on studying the significance of nuclear expression of survivin in disease outcome, although these reports pointed out the fact that survivin could be expressed in either cytoplasm or nuclei. [15][16][17][18][19] Two of these 5 studies reported that overall, survivin expression was an unfavorable prognostic factor. 16,18 The localization of survivin in nuclei or cytoplasm was determined by immunohistochemistry (IHC) in all 19 reports. One of the 19 publications alternatively carried out Western blots using cell lysates from the fractionated cytoplasm and nuclei for the confirmation of survivin localization. 5 In addition, Nakagawa et al. 20 reported recently that nuclear localization of survivin, as well as cytoplasmic in some cases, was essentially found in acute lymphocytic leukemia (ALL) cells whereas cytoplasmic expression of survivin was predominantly showed in chronic lymphocytic leukemia (CLL) cells. The significance, however, was not investigated. Nuclear expression of survivin is an unfavorable prognostic markerIn hepatocellular carcinoma (HCC), studies from Ito et al. 1 indicated that 14 of 20 (70%) HCC tissues showed nuclear staining of survivin, whereas non-tumor tissues showed little survivin staining. Nuclear survivin expression strongly correlated with the proliferation index. 1 Similarly, studies from Moon et al. 4 showed that 22 of 35 (63%) survivin-positive specimens (total ϭ 47) showed punctate nuclear staining in HCC cells. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC specimens with nuclear survivin expression showed the highest PCNA (proliferating cell nuclear antigen) labeling index and correlated with tumor cell de-differentiation. 4 Recently, Fields et al. 8 reported that immunohistochemical analyses of 72 hep...

Prognostic Significance of Survivin and Caspase-3 Immunohistochemical Expression in Patients with Diffuse Large B-cell Lymphoma Treated with Rituximab and CHOP

“…These results may in part correspond to the pivotal study of survivin in DLBCL by Adida et co-workers, who demonstrated an adverse role of cytoplasmic survivin on 222 patients [10]. Other reasons that may influence results are different clones of antisurvivin antibody used and differences in tumor tissue processing [5]. In contrast to all previous studies of survivin in DLBCL, our patients were treated with rituximab and CHOP.…”

“…Although IAPs were originally described as caspase inhibitors, more recent studies identified survivin as a regulator of mitosis, a broad cytoprotective factor, and an effector of cellular adaptation to stress [4]. Survivin expression was detected in various tumors and mostly correlated with inferior outcome [5]. Immunohistochemical expression of survivin was also investigated in DLBCL [6][7][8][9][10][11][12][13].…”

Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder

“…49,50 It has been proposed that variations in immunostaining and interpretation might be among the contributing factors to these conflicting results. 51 The distinct nuclear and cytoplasmic staining in our study is unequivocal, and we provided detailed quantitative data on the nuclear staining than Survivin nuclear index in urothelial carcinoma W Yin et al previous reports. Our data clearly showed that BIRC5 nuclear labeling index, but not cytoplasmic staining, was significantly associated with tumor grade, stage, and poorer prognosis for Ta/T1 urothelial carcinomas.…”

“…Different prognostic significance of BIRC5 nuclear labeling in several tumor types has been reported in recent years, [45][46][47][48][49][50] as summarized in reference Li et al 51 For example, correlation of BIRC5 nuclear (but not cytoplasmic) staining with poor prognosis has been reported in ependymoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, mantel cell lymphoma, and non-small cell lung cancer. [45][46][47][48] Paradoxically, BIRC5 nuclear staining was reported to be associated with better prognosis in gastric cancer and breast cancer.…”

Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients

“…The ratio of detection of cytoplasmic to nuclear reactivity can vary depending on the antibodies used (Fortugno et al, 2001). A recent review of the significance of survivin in cancers generally (Li et al, 2005) identified more studies in which it was found to relate to poorer prognosis, and recommended that for technical reasons nuclear and cytoplasmic staining should not be considered separately, the approach used in the present study.…”