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Study of the expression of Survivin in relation to E-Cadherin and their significance in colorectal carcinoma. An immunohistochemical and clinicopathological study

El Sabaa, Bassma Mohameda; Arafat, Walid Ossmanb; Maksoud, Walid Abdelc

doi: 10.1097/01.XEJ.0000406590.87075.6c
ORIGINAL ARTICLES
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Objective Several therapeutic modalities have been used in the treatment of colorectal carcinoma (CRC); however, a complete cure has not been achieved. The development of CRC involves accumulated genetic alterations with progressive inhibition of apoptosis and increased tumor cell invasion. The expression of Survivin, a member of the inhibitor of apoptosis protein family, and E-Cadherin, the prime mediator of epithelial intercellular adhesion, has been studied in different malignancies. Here, we study their expression in colorectal adenocarcinoma sections in relation to different clinicopathological parameters including the length of progression-free survival.

Methods Immunohistochemical staining for Survivin and E-Cadherin was carried out on paraffin-embedded tissue sections. The results were statistically correlated with different clinicopathological parameters and the length of progression-free survival.

Results This retrospective study included 44 patients of colorectal adenocarcinoma. Of these, 14 (31.8%) men and 30 (68.2%) women were operated upon for CRC, with ages ranging between 26 and 80 years (mean 57.27±14.08 years). Survivin was expressed in all sampled cases (100%). Cytoplasmic Survivin staining was detected in 42 cases (95.5%) versus only two cases (4.5%) showing nuclear expression. E-Cadherin staining was positive in 42 cases (95.5%), with cytoplasmic expression in 24 cases (54.5%) and both membranous and cytoplasmic expression in 14 cases (31.8%). Neither Survivin nor E-Cadherin demonstrated a statistically significant relation to any of the clinicopathological parameters studied. The expression of E-Cadherin tended to increase as that of Survivin increased, (Spearman ρ=0.28, P=0.06). Survivin and E-Cadherin expression scores were not related to the length of progression-free survival; however, E-Cadherin cytoplasmic expression was statistically related (P=0.02) to longer progression-free survival unlike any studied pattern of Survivin expression.

Conclusion Survivin was expressed in all studied cases of CRC. The expression of E-Cadherin does not decrease but shifts from the membrane to the cytoplasm. Neither Survivin nor E-Cadherin expression correlated with clinicopathological parameters. There is a significant correlation between cytoplasmic expression of E- Cadherin (but not Survivin) and longer disease-free survival. The expression of Survivin tended to correlate with that of E-Cadherin.

Departments of aPathology

bOncology

cColorectal Surgery, Alexandria Faculty of Medicine, Alexandria, Egypt

Correspondence to Bassma El Sabaa, MD, Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt Tel: +203 427 3249/203 429 4963; fax: +203 487 3076; e-mail: bassma_el_sabaa@yahoo.com

Received June 5, 2011

Accepted June 20, 2011

Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality in industrialized Western countries (Elzagheid et al., 2006). In Egypt, CRC represents only 6.5% of all cancers (El-Bolkainy, 2005) characteristically, with higher rates of young-onset disease (Soliman et al., 2001).

The prognosis of CRC patients depends strongly on the development of recurrence and/or metastasis. An optimal strategy would be to apply reliable criteria for predicting recurrence and identifying tumors that will respond to chemotherapy (Elzagheid et al., 2006).

The regulation of apoptotic cell death may have a profound effect on the pathogenesis and progression of colon cancer (Gianani et al., 2001). The development and progression of CRC involves unregulated epithelial cell proliferation with accumulated genetic alterations and ultimate malignant transformation with progressive inhibition of apoptosis (Chen et al., 2004). In contrast to Bcl-2, Survivin does not appear to be functionally involved in the physiological regulation of apoptosis in adult colonic epithelium but is prominently expressed in CRC and several other malignancies, (Sarela et al., 2000).

Survivin is a 16.3 kDa (142-amino-acid) protein encoded by a gene on chromosome 17q25 (Xie et al., 2006). It is the smallest member of the inhibitor of apoptosis protein family (Mikami, 2003; Stauber et al., 2007), and it blocks apoptosis through an effect on caspase-9 (Cohen et al., 2003). Survivin is expressed during development and in proliferating cells, but is largely undetectable in most differentiated tissues, in the absence of stress conditions (Xie et al., 2006; Stauber et al., 2007). Correction of attachment errors between chromosomes and the mitotic spindle in addition to its role in inhibiting apoptosis are among its basic functions (Stauber et al., 2007). Survivin is reported to be expressed in a variety of blood and solid tumors, where its expression has been correlated with resistance to therapy-induced apoptosis and shorter survival (Chen et al., 2004; Stauber et al., 2007).

The metastatic cascade starts with a breakdown of the epithelial integrity, thereby enabling tumor cells to invade the surrounding stroma, penetrate into blood or lymphatic vessels, and finally seed the appropriate target organs (Elzagheid et al., 2006).

Adhesion molecules are surface receptors, involved in intercellular interactions and cellular–extracellular interactions. They are divided into four main groups: cadherins, integrins, selectins, and a class of immunoglobulins. E-Cadherin is a 97-kDa transmembrane glycoprotein (Elzagheid et al., 2006) encoded by the E-Cadherin gene (CDH1) located on chromosome 16q22.1 (Berx and Van Roy, 2001).

E-Cadherin is the prime mediator of epithelial cell–cell adhesion by calcium-dependent interactions through its role in inducing and maintaining epithelial integrity. The cytoplasmic domain of E-Cadherin interacts with catenins; the complex thus formed then acts as an invasion suppressor (Debruyne et al., 1999). A role in intracellular signaling in normal epithelial has been suggested (Berx and Van Roy, 2001).

Exploration of the functional potential of E-Cadherin can allow a deeper understanding of the pathogenesis of metastases, thereby providing new perspectives in the diagnosis and therapy of different types of cancer (Guzińska Ustymowicz et al., 2004). In general, increased E-Cadherin expression causes a tighter association of tumor cells, (Soliman et al., 2001; Abd El Hameed, 2005; Elzagheid et al., 2006). Partial or total loss of E-cadherin expression may free cancer cells (Berx and Van Roy, 2001; Khoursheed et al., 2003). In most human gastrointestinal cancers, the E-Cadherin/Catenin or related complexes are disturbed (Debruyne et al., 1999).

This study was designed to evaluate the expression of Survivin and E-Cadherin in colon carcinoma, exploring their mutual relation and the correlation of their expression to clinicopathological characteristics and patients’ prognosis.

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Materials and methods

Patients and specimens

This retrospective study, approved by the Ethics Committee of Alexandria Faculty of Medicine, consisted of a consecutive series of 44 colorectal adenocarcinomas with complete histopathological data available. Patients were diagnosed and treated at the Alexandria University Hospital, Alexandria, Egypt, between June 2006 and December 2006. All tissue samples were formalin-fixed and paraffin-embedded. Hematoxylin and eosin-stained slides, pathological reports, and other medical records were reviewed to confirm the diagnosis.

No patients received neoadjuvant treatment. Survival data were available for 24 patients only for 48 months. All patients survived the follow-up period.

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Immunohistochemical staining

Immunohistochemical staining was carried out using the avidin–biotin method with a commercially available kit (Ultravision Detection System, Thermo SCIENTIFIC, Fremont, California, USA). Four-micrometers thick sections on coated slides were routinely deparaffinized by heating at 55°C for 30 min and by three 5-min washes with xylene. Tissues were rehydrated by a series of 5-min washes in 100, 90, and 70% ethanol and phosphate-buffered saline. Antigen retrieval was performed by microwaving the samples for 20 min for both E-Cadherin and Survivin at full power in 10 mmol/l sodium citrate buffer (pH 6.0), which was then left to cool to room temperature. Endogenous peroxidase activity and nonspecific binding were blocked. The primary mouse monoclonal anti-E-Cadherin antibody 36B5 (Thermo Fisher Scientific, Catalogue number MS-1479-R1) was purchased ready to use and the primary rabbit polyclonal anti-Survivin antibody (Thermo Fisher Scientific, Catalogue number RB-9245-PO) was diluted 1 : 200. Antibodies against both E-Cadherin and Survivin were incubated at room temperature for 1 h. After a series of washes in phosphate-buffered saline, sections were incubated with a biotinylated goat secondary antibody (10 min) and then horseradish peroxidase-streptavidin (10 min), followed by developing with a 3, 3′-diaminobenzidine substrate (10 min) and counterstaining with Mayer’s Hematoxylin. Slides were dehydrated and sealed with coverslips. Tonsillar squamous epithelium was used as a positive control of E-cadherin and prostate carcinoma tissue as a positive control of Survivin. Negative controls were obtained by excluding the primary antibody during incubation.

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Evaluation of E-Cadherin immunostaining

Approximately 10 fields per section were observed at low power (×100). E-Cadherin expression was evaluated in normal and malignant epithelia. The expression of E-Cadherin was scored both in terms of the percentage and the intensity of staining. For percentage, the following grades were used: negative – no detectable staining; one: expression detected in less than one-third of the cells; two: expression detected in one-third to two-thirds of the cells; and three: expression detected in more than two-thirds of the cells. The intensity of staining was graded as negative 0; weak (1); moderate (2); or strong (3). A combined weighted score for E-cadherin expression was obtained by multiplying the percentage score by the intensity score. For all positive cases, localization of staining to the cell membrane, cytoplasm, or both (mixed) was assessed (Khoursheed et al., 2003).

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Evaluation of Survivin immunostaining

Survivin expression was scored both in terms of the percentage and the intensity of staining, which were later multiplied to obtain a weighted score. Five fields were observed at low power (×100). Positively staining cells were expressed in terms of percentage of the total number of cells in the lesion and then assigned to one of five categories: 0, less than 5%; 1, 5%–25%; 2, 25%–50%; 3, 50%–75%; and 4, greater than 75%. We regarded the staining as positive in cases with cytoplasmic and nuclear positivity. Intensity was scored as weak, 1; moderate, 2; or intense, 3 (Mikami, 2003).

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Statistical analysis

The mean Survivin weighted score as well as the mean E-Cadherin weighted score were compared among grades, groups of different nodal status, and groups of different tumor invasion status using analysis of variance. The correlation between weighted E-Cadherin and Survivin scores was determined using the Pearson correlation. The log-rank test was used in Kaplan–Meier analysis to compare progression-free survival between E-Cadherin and Survivin scores as well as their patterns of expression. Number of events and percent of censored cases were calculated. Statistical analysis was performed using SPSS version 13.0 (SPSS, Chicago, Illinois, USA). The level of significance was set at 5%.

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Results

There were 14 (31.8%) male and 30 (68.2%) female patients, with ages ranging between 26 and 80 years (mean: 57.27±14.08 years).

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Survivin expression

Survivin was expressed in all sampled cases of tumor tissue (100%). Expression was noted in the normal mucosa of four cases (9%) Fig. 1a. Regarding Survivin percentage expression, two cases (4.5%) recorded score 1, six cases (13.6%) recorded score 2, 12 cases (27.3%) recorded score 3, and 24 cases (54.5%) recorded score 4. Survivin expression intensity readings were 1 in two cases (4.5%)-Fig. 1b, 2 in 30 cases (68.2%)-Fig. 1c and d, and 3 in 12 cases (27.3%)-Fig. 1e. The weighted scores ranged between 2 and 12, with a mean of 7.45±2.86

Fig. 1

Fig. 1

Survivin staining was cytoplasmic in 42 cases (95.5%) and nuclear in two cases (4.5%)-Fig. 1f. Expression was always cytoplasmic in normal mucosae.

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E-Cadherin expression

Normal mucosa of all sampled cases was positive to E-Cadherin immunostaining, invariably in a membranous location Fig. 2a. E-Cadherin staining was positive in 42 cases (95.5%) of tumor samples and negative in two (4.5%). The E-Cadherin pattern of expression was membranous in four cases (9.2%), cytoplasmic in 24 cases (54.5%), and both (membranous and cytoplasmic) in 14 cases (31.8%).

Fig. 2

Fig. 2

Regarding the percentage of tumor cells expressing E-Cadherin, two cases did not express E-Cadherin (4.5%) score 0, eight cases (18.2%) scored 1, 20 cases (45.5%) scored 2, whereas 14 cases (31.8%) scored 3. The intensity of E-Cadherin expression was 0 in two cases (4.5%), 1 in 14 cases (31.8%) Fig. 2b, 2 in 26 cases (59.1%)-Fig. 2c, and 3 in two cases (4.5%) Fig. 2d. E-Cadherin-weighted scores ranged between 0 and 9, with a mean of 3.68±2.25.

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Relation between Survivin expression and clinicopathological variables

The survivin weighted score did not show a statistically significant relation with tumor grade, depth of invasion, or nodal invasion (P=0.35, 0.30, 0.48, respectively). Table 1

Table 1

Table 1

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Relation between E-Cadherin expression and clinicopathological variables

There was no statistically significant relation between E-Cadherin weighted score and the depth of tumor invasion or nodal invasion (P=0.10, 0.07); however, the score tended to increase with increasing tumor grade and yet the relation did not reach statistical significance (P=0.06). Tables 2 and 3.

Table 2

Table 2

Table 3

Table 3

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Discussion

Inhibition of apoptosis is one of the basic pathogenetic steps implicated in carcinogenesis, enabling cells to prolong their survival, avoid immune surveillance, and resist cytotoxic therapies. Survivin, a member of the inhibitor of apoptosis protein family, is believed to play a role in progression of cancer and therapeutic resistance (Cohen et al., 2003).

In this work, all studied cases (100%) of CRC were immunopositive for Survivin. Other researchers reported figures of 79% (Chen et al., 2004), 78.5% (Jiang et al., 2004), and 100%. (Gianani et al., 2001).

Strong expression of Survivin has been reported in a range of solid malignancies including lung, stomach, breast, esophagus, colon, pancreas, urinary bladder, prostate, endometrium, uterine cervix, ovary, neuroblastoma, melanoma, and nonmelanomatous skin cancers. Expression has been reported in hematopoietic malignancies as well (Cohen et al., 2003).

Immunopositivity to Survivin varies according to the type of malignancy from 34% of gastric carcinomas to 93% of melanomas. Abd El Hameed (2005) explains this organ-dependent differential expression by intrinsic biological differences pertinent to the tumor studied and the type of antibody used (the higher affinity of polyclonal antibodies compared with monoclonal antibodies).

Whereas some authors claim that normal colonic mucosa does not express Survivin (Jiang et al., 2004; Abd El Hameed, 2005), others were able to detect Survivin mRNA transcripts (using RT-PCR) in histologically normal mucosa. Their conclusion was that Survivin expression in this setting might represent an ‘intermediate’ state marking the risk of neoplastic transformation (Sarela et al., 2000). Still, other researchers -ourselves included- were able to immunohistochemically detect Survivin in normal colonic mucosa. In this work, normal mucosae of four cases (9%) displayed uniform staining, a finding that agreed with that of Gianani et al. (2001).

In this work, as in others’ work (Kawasaki et al., 1998; Jiang et al., 2004; Abd El Hameed, 2005; Ponnelle et al., 2005; Li et al., 2007), no relation was found between Survivin expression on the one hand and patient’s sex, tumor grade, lymph node metastasis, or depth of invasion on the other. In the same context, Chen et al., 2004, working on the gene expression level, obtained the same result.

Conversely, other researchers (Lee et al., 2009; Na et al., 2009) found a statistically significant correlation between Survivin expression and lymph node metastasis and depth of tumor invasion. In their attempt to explain these contradictory reports, Brennan et al. (2008) claimed that this might stem from the varying specificity of the antibodies used or the inherent inter/intraobserver variability in interpreting Survivin immunostained sections.

In this study, like in others (Cohen et al., 2003; Lee et al., 2009), no relation was found between Survivin expression and length of disease-free survival; however, others could prove such a relation (Kawasaki et al., 1998). We did not establish correlations between Survivin expression and clinicopathological variables. This could be ascribed to the heterogeneity of studied cases vis-a-vis the clinical stage. In agreement with this, Adida et al. (1998) reported that the predictive value of Survivin expression was limited to patients with stage II CRC (Chen et al., 2004). Their finding was ‘later’ confirmed in Na et al.’s (2009) work, when they stated that ‘on stage wise analyses of patient survival, the Survivin expression was significantly correlated with overall survival and disease free survival, especially in stage II colorectal carcinomas.’

Analysis of the subcellular expression of Survivin is claimed by some authors to be of prognostic implication in stratifying patients with CRC. (Ponnelle et al., 2005; Stauber et al., 2007).

In this work, 95.5% of cases expressed Survivin in the cytoplasm, whereas only 4.5% showed nuclear expression. In line with our findings are those by Wang et al. (2010), who report that the subcellular localization was invariably in the cytoplasm. However, our figures strongly contrasted with those reported by Ponnelle et al. (2005), where 39% of colorectal tumors expressed Survivin in the nucleus and 41% in the cytoplasm.

In fact, according to Li et al. (2005), in their detailed review on the significance of subcellular localization of Survivin, among the 19 publications pertinent to Survivin subcellular localization in cancer tissues, nine proved nuclear expression as an unfavorable prognostic marker, whereas five proposed the reverse.

Several arguments have been put forward to explain these conflicting results. It has been proposed that procedural variations in immunostaining (Yin et al., 2006) and/or variable criteria used to label a tumor as nuclear Survivin or cytoplasmic Survivin positive might have played a role. (Yin et al., 2006; Qi et al., 2009) The difference in localization may also be ascribed to the tumor type and/or the biopsies examined, whether pretherapeutic or posttherapeutic (Qi et al., 2009). Li et al. (2005) provide another explanation relating to the presence of a number of splicing variants having different patterns of subcellular localization and hence variable biological roles. However, the currently available anti-Survivin antibodies recognize all the variants due to the existence of a common amino-terminal peptide. (Li et al., 2005).

Cohen et al. (2003) summarized the biochemical basis of subcellular localization in the amino-acid sequence of the carboxy-terminal domain of Survivin claimed to be responsible for its cytoplasmic localization and the nuclear localization of its splicing variant, Survivin _ Ex 3.

Distinct roles have been assigned to Survivin in each subcellular compartment. By maintaining the integrity of the mitotic spindle, nuclear Survivin displays its relation to the cell cycle (Cohen et al., 2003; Xie et al., 2006) being a prerequisite for cancer cell proliferation (Li et al., 2005; Stauber et al., 2007), whereas cytoplasmic localization of Survivin may promote its cytoprotective function by facilitating its interplay with the apoptotic machinery in cancer cells, thereby conferring an antiapoptotic effect (Stauber et al., 2007).

In the current work, no statistically significant relation was established between any pattern of subcellular localization of Survivin and length of progression-free survival (P=0.34). In the same context, Ponnelle et al. (2005) were able to prove that a high level of Survivin cytoplasmic expression was associated with better survival in patients with CRC, which contrasted with the findings of others (Cohen et al., 2003; Abd El Hameed, 2005), who demonstrated the reverse.

Acknowledging such a disparity in biological roles governed by variations in subcellular localization, some authors advocate quantifying not only the absolute expression levels of Survivin but also applying an immunoreactive score for cytoplasmic and nuclear forms (Stauber et al., 2007). Defining levels of nuclear versus cytoplasmic survivin might be of more prognostic relevance in CRC compared to measuring the total protein amount (Qi et al., 2009).

Unraveling the mechanisms of tumor cell invasion may aid the development of new treatment modalities that can hopefully arrest local invasion and metastatic spread of cancer. (Lee et al., 2009) In this context, research has long focused on elucidating the role of E-Cadherin, the prime mediator of epithelial intercellular adhesion (Debruyne et al., 1999).

Normal colonic mucosa shows a diffuse continuous ‘clean’ membrane immunopositivity along the lateral cell borders (Debruyne et al., 1999; Elzagheid et al., 2006)

The previous papers state the expected, logical loss of E-Cadherin expression in CRC (Dorudi et al., 1993; Khoursheed et al., 2003; Tsanou et al., 2008). Some authors attribute this loss primarily to gene silencing by hypermethylation of the promotor region (El Bahrawy et al., 2001). The loss of E-cadherin expression is associated with higher grade and more advanced stage in carcinomas of the breast, prostate, and urinary bladder (Khoursheed et al., 2003).

Over the years, different research groups have started to focus on a new theme, that is, the alteration in the subcellular localization of E-Cadherin from the membrane to the cytoplasm rather than an overall loss of staining (Aust et al., 2001; El Bahrawy et al., 2001; El Bahrawy et al., 2002; Guzińska Ustymowicz et al., 2004). Possibly, the ability to detect the marker in carcinomas may be related to technical advances in the sensitivity of the antibodies used. In accordance, cytoplasmic E-Cadherin was detected in 95.5% of our cases. Guzińska Ustymowicz et al. (2004) reported the same finding, claiming that the mere shift from membrane to cytoplasm leads to loss of function.

As an explanation for the cytoplasmic redistribution of E-Cadherin in colonic carcinoma, several possible mechanisms were proposed including downregulation of its tyrosine phosphorylation, (Nawrocki et al., 1998; Aust et al., 2001) increased E-Cadherin production rate, or failure to anchor to the membrane. The latter may be ascribed to alterations in a, ß, and y-catenins that link the E-Cadherin molecule to the actin cytoskeleton (Dorudi et al., 1993; Khoursheed et al., 2003). Other researchers add posttranslational modification as a possible factor governing changes in antigen availability (Dorudi et al., 1993; Elzagheid et al., 2006).

We report a statistical correlation (P=0.02) between the cytoplasmic expression of E- Cadherin and a longer disease-free survival in colon carcinoma cases studied. This contrasted with the work of Elzagheid et al. (2006), who claimed that ‘cytoplasmic expression more closely predicted disease recurrence and that reduction of membranous expression appeared to portend a poorer prognosis.’

This study found no significant correlation between E-Cadherin expression scores and the various clinicopathological variables, a finding that was reported previously (Khoursheed et al., 2003; Elzagheid et al., 2006). However, other researchers found that changes in E-Cadherin expression could correlate with a strong invasive potential (Tsanou et al., 2008).

In the current work, the expression of Survivin tended to correlate with that of E-Cadherin but statistical significance was not reached (P=0.06). We postulate that if a larger sample size is used, a positive relation might be established. Sarela et al. (2000) considered metastasis (and hence cell detachment from the surrounding matrix) and suppression of apoptosis to be parallel events. Detachment, according to Sarela et al., would trigger apoptosis in most adherent cells. Cells that express antiapoptosis genes (as Survivin) will be advantageous for survival and would continue to replicate.

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Conclusion

In conclusion, Survivin was expressed in all cases of CRC studied. The expression of E-Cadherin does not decrease but shifts from membrane to cytoplasm. Neither Survivin nor E-Cadherin expression correlated with clinicopathological parameters. There is a significant correlation between the cytoplasmic expression of E-Cadherin (but not Survivin) and longer disease-free survival. The expression of Survivin tended to correlate with that of E-Cadherin.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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