Background Cancer stem cells have been investigated as new targets for colorectal cancer (CRC) treatment. We recently reported that CD133+ colon cancer cells showed chemoresistance to 5-fluorouracil through increased survivin expression and proposed the survivin inhibitor YM155 as an effective therapy for colon cancer in an in vitro study. Here, we investigate the relationship between survivin and CD133 expression in surgically resected CRC to identify whether the results obtained in our in vitro study are applicable to clinical samples.
Methods We performed immunohistochemical staining for survivin and CD133 in surgically resected tissue from 187 stage II or III CRC patients. We also comparatively analyzed apoptosis according to survivin and CD133 expression using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling.
Results The results of the Mantel-Haenszel test established a linear association between nuclear survivin and CD133 expression (p = .018), although neither had prognostic significance, according to immunohistochemical expression level. No correlation was found between survivin expression and the following pathological parameters: invasion depth, lymph node metastasis, or histologic differentiation (p > .05). The mean apoptotic index in survivin+ and CD133+ tumors was higher than that in negative tumors: 5.116 ± 4.894 in survivin+ versus 4.103 ± 3.691 in survivin– (p = .044); 5.165 ± 4.961 in CD133+ versus 4.231 ± 3.812 in CD133– (p = .034).
Conclusions As observed in our in vitro study, survivin expression is significantly related to CD133 expression. Survivin may be considered as a new therapeutic target for chemoresistant CRC.
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BACKGROUND DNA topoisomerase II-alpha is linked with active cell proliferation in mammalian cells. The aim of this study was to examine the relationship between the expression of DNA topoisomerase II-alpha as a proliferating marker, and the expression of Ki-67 and apoptosis in urothelial carcinoma of urinary bladder based on World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification.
METHODS 73 urothelial carcinomas of the urinary bladder after transurethral resection and 25 carcinomas after radical cystectomy were investigated for histologic grading based on WHO and WHO/ISUP consensus classification. Formalin fixed, paraffin embedded tissue of 98 specimens from 73 patients were immunohistochemically stained for DNA topoisomerase II-alpha and Ki-67, and in situ TdT-mediated dUTP-biotin nick end labeling method for evaluation of apoptotic cells was performed. For each case, a DNA topoisomerase II-alpha, Ki-67, and apoptotic indices were determined.
RESULTS The histologic grades of 73 cases based on the WHO grading system were 21.9% (16 cases) in grade 1, 65.8% (48 cases) in grade 2, and 12.3% (9 cases). 5.5% (4 cases) of papillary neoplasm of low malignant potential, 47.9% (35 cases) of urothelial carcinoma of low grade, and 46.6% (34 cases) in urothelial carcinoma of high grade were reclassified using the WHO/ISUP consensus classification.
Histologic grades based on two grading systems were correlated to invasion and stage (p<0.05). DNA topoisomerase II-alpha, Ki-67, and apoptotic indices were correlated to histologic grades based on two grading system and invasion.
Also, the correlation of DNA topoisomerase II-alpha and Ki-67 indices, and DNA topoisomerase II-alpha and apoptotic indices were significant, respectively.
CONCLUSIONS DNA topoisomerase II-alpha appears to be an useful marker for assessing the proliferation potential of urothelial carcinoma of in the urinary bladder.
BACKGROUND The expression of the inhibitor of apoptosis proteins (IAPs) family has not been fully investigated in colorectal carcinomas. This study investigated IAP expression in colorectal carcinomas and assessed their prognostic significance. METHODS Livin, XIAP, and SMAC/DIABLO expression was assessed by immunohistochemistry in 159 colorectal carcinomas. Correlations between protein expression and clinicopathological features were evaluated. The survival data analysis was estimated according to the Kaplan-Meier method. RESULTS Increased expression of IAPs in cancer tissues compared to surrounding nonneoplastic counterparts was observed in 67 cases (42.1%) for Livin, 50 cases (31.4%) for XIAP, and 68 cases (42.8%) for SMAC. A significant correlation was found between Livin expression and tumor differentiation, and SMAC expression and tumor location. The recurrence-free and overall survival of patients with low Livin expression were inferior to those of patients with high Livin expression (p=0.054 and 0.095, respectively).
High XIAP expression was significantly associated with shorter progression-free survival (p= 0.041). CONCLUSIONS Our study demonstrated that altered expression of IAP family members, including Livin, XIAP, and SMAC, is frequent in colorectal carcinoma. This result suggests that high Livin expression and low XIAP expression may be a favorable prognostic implication related to patient survival.
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BACKGROUND pAkt (the phosphorylated form of the proto-oncogene protein c-akt) and survivin (human BIRC5 protein) are candidate apoptosis-related molecules that may be responsible for cancer progression.
The aim of this study was to determine the expression of pAkt and survivin in malignant stomach neoplasm, and their value as prognostic indicators of cancer. METHODS The expression of pAkt and survivin in 144 cases of gastric cancer was detected by immunohistochemistry and compared with established clinicopathological parameters and prognosis of this disease. RESULTS Expression of pAkt showed significant correlations with depth of invasion, lymph node and distant metastasis, as well as the stage (p < 0.05 for all three correlations), but not with the Lauren classification. Survivin expression closely correlated with histological type, Lauren classification, depth of invasion, metastasis, and stage (p < 0.05 for all). The overall survival of patients with pAkt/survivin expression was inferior to that of patients with loss of pAkt/survivin expression. Cox multivariate analysis demonstrated a significant correlation between stage (p = 0.04), survivin expression (p = 0.02), and prognosis. CONCLUSIONS Patients with pAkt/survivin expression in gastric cancer are at increased risk of cancer-related mortality via the apoptosis resistance pathway. Expression of pAkt and survivin could be used as a prognostic indicator for gastric cancer.
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BACKGROUND Survivin, a novel antiapoptotic gene has been linked with tumor development and progression in various human carcinomas including gastric carcinomas. The aim of this study was to evaluate the expression of survivin in gastric carcinoma and its correlation with tumor cell proliferation and apoptosis. METHODS: Expression of survivin was evaluated immunohistochemically in 84 surgically resected gastric carcinomas. Tumor cell apoptosis was evaluated with terminal deoxynucleotidyl transferase (TdT) mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), and Ki-67 immunostaining was used for evaluation of tumor cell proliferation. RESULTS: Expression of survivin was noted in 53.6% of the gastric carcinomas, and was significantly associated with depth of invasion, status of lymph node metastasis or tumor stage (p=0.022, 0.034, 0.040, respectively). There was an inverse correlation between survivin expression and apoptotic index (p=0.015). But there was no significant correlation between survivin expression and Ki-67 labeling index (p=0.430). CONCLUSIONS: These results suggest that survivin expression may contribute to tumor development and progression by inhibiting apoptosis in human gastric carcinoma.
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Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression SOO-AH KIM, RAN HONG Oncology Letters.2014; 7(5): 1589. CrossRef
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma which responds well to conventional chemotherapy. However, quite a few patients have a recurrence with more aggressive forms after completion of therapy. Multidrug resistance proteins (MRP) are related to this process in several ways such as cell cycle alteration and modulation of apoptosis. METHODS: We investigated the expression of P-glycoprotein (Gp), one of the well-known MRP, as well as apoptosis associated proteins in DLBCL. Immunohistochemical staining for Gp, p53, Bcl-2, Ki-67, active caspase 3 and FADD was done in forty DLBCL cases. The association between MRP and apoptosis associated proteins to clinical findings was also tested. RESULTS: Twenty-nine patients out of 40 (73%) with DLBCL were positive for Gp, and 26 cases (65%) had a strong positive for Gp. Gp expression was stronger in high-grade lesions than in low-grade lesions and was associated to Bcl-2 expression. However, we could not find an adverse impact of Gp expression on patients' overall survival or relapse free survival rate. CONCLUSIONS: Our study revealed a high frequency of expression for Gp in DLBCL with a possible relationship between the expressions of Gp to apoptosis associated proteins.
Melanosis coli is characterized by a dark brownish discoloration of the colonic mucosa. Its pathogenesis is still unknown. Recently it was proposed that the apoptosis of mucosal epithelium due to habitual use of laxatives play an important role for induction of melanosis coli. We studied clinicopathologic aspects of 12 cases of melanosis coli and analysed the histochemical and immunohistochemical characteristics of them. Results are as follows. : Mean patient's age was 53.5, and the male:female ratio was 4:8.
Nine patients had a history of constipation, and all of these had administrated various kinds of laxatives. The severity of discoloration was correlated with the duration of constipation and age. There was no difference of anatomical distribution in colon. Other remarkable mucosal lesions were not accompanied. On pathologic examination, all cases showed frequent yellow-brown pigment laden cells in lamina propria. These pigments were positive for periodic acid Schiff stains, Fontana Masson stains, and Victoria blue stains, however they were negative for prussian blue stain.
On immunohistochemical stainings pigmented cells were positive for CD68, and negative for S-100 protein and neuron specific enolase. These results indicate that they are macrophages. On ultrastructural examination pigmented cytoplasms were filled with variable sized electron dense granules including irregulary round deformed membranous structures, lipid vacuoles. Apoptosis of mucosal epithelium was noted in 5 cases. These findings suggest that apoptosis is the significant pathologic process in the progression of some cases of melanosis coli.
Transglutaminase(TGase) is a calcium dependent enzyme that catalyse and acyl transfer reaction forming epsilon-(gamma-glutamyl)-lysine cross linkage. the major known effect of TGase is its important role in the programmed cell death manifested in the granular layer of the skin and acidophilic bodies in the viral hepatitis and neoplastic processes. The enzyme activity, immunohistochemical reaction using polyclonal antibodies against cytosolic TGase C, light and electron microscopic studies and TdT staining of the transplanted fibrosarcoma cells in C3H mouse with radiation therapy were done. The presence of TGase was detected immunohistochemically by avidin-biotin peroxidase complex (ABC) method Apoptosis were significantly induced after irradiation dependent with time factors and irradiation doses, resulted in marked and confluent tumor cell loss. Highest activity of the cytosolic form of TGase was noted at 24 hours and decrease after then while membrane bounded form of the TGase showed no significant changes. Immunohistochemical staining revealed strong positive reaction in the sarcoma cells in diffuse fasion and around the necrotic foci in the cytoplasm.
Terminal dideoxynucleotidyl transferase(TdT) staining revealed increasing numbers of apotptic cells from two hours after irradiation. In the mechanism of decreasing tumor size and cell death in radiation therapy, apoptosis plays an important role and during that process transglutaminse might do some irreversible cross-linking effects of cytoplasmic proteins causing cell death in part.
Either increased cellular proliferation or decreased death might result in an expansion of their numbers in the oncogenic process. Cellular apoptosis represents an autonomous suicide pathway that helps to restrict the cell number. However bcl-2 and mutant p53 inhibit programmed cell death. To determine whether the bcl-2 gene is activated during colorectal tumorigenesis and whether it has any relationship with p53 and apoptosis, we studied the expression of bcl-2 and p53 in the normal colonic mucosa, in the adenomatous polyps and in the adenocarcinomas using the immunohistochemical method. Also we evaluated the status of apoptosis using the in situ end labeling method. The bcl-2 immunoreactivity was restricted to the basal epithelial cells of all normal colonic mucosa and they were expressed in all adenomas and 86% of adenocarcinomas, especially in the superficial lesion of some tumors. Mutations of p53 were not found in the normal colonic mucosa, but they were present in dysplastic cells of adenomas (52%) and in cancer cells of the adenocarcinomas (47%). Apoptosis was confined to the tips of the normal colonic mucosa. It was more easily detected in the p53-positive adenomas than in the p53-negative adenomas (p=0.010). In the adenocarcinomas, the findings of apoptotic process are not related with p53 mutation (p=0.3) and bcl-2 expression (p=0.187). p53 and bcl-2 are probably one step of several apoptotic processes in the adenocarcinomas.
Apoptosis (or programmed cell death) is defined by morphologic changes induced by a spectrum of physical and chemical agents. resulting in non-pathologic cell loss, which is relevant to a range of biological processes, including differentiation, development, maturation, and injury of cells as well as immunologic function. In this study, we examined the frequency of apoptotic bodies and mitoses (apoptotic and mitotic indices) in the tissue samples of 35 patients of prostatic carcinoma, which were grouped according to the Gleason scores, and 5 cases of benign prostatic hyperplasia. The indices were determined as the numbers of apoptotic and mitotic bodies per 100 tumor cells in hematoxylin eosin stained section. The apoptotic bodies were confirmed by the in situ nick end labelling method. The apoptotic and mitotic indices were observed more frequently in prostatic carcinoma than the benign hyperplastic prostatic tissues with a positive correlation between the frequency of apoptotic bodies and Gleason scores in prostatic cancer. In conclusion, an increased programmed cell death was correlated with the increasing malignant potential (higher Gleason scores) in prostatic cancer.
This study was undertaken to know the extent of apoptosis, expression of bcl-2 and proliferating cell nuclear antigen (PCNA) in uterine cervical intraepithelial neoplasia (CIN; 15 cases) and invasive carcinoma (27 cases) and to evaluate them as a prognostic marker. Apoptosis was analysed by using the in situ apoptosis detection kit and bcl-2 and PCNA were detected by the immunohistochemical method. The results were as follows: Apoptotic indices (AI) in the invasive carcinoma (mean: 4.3) were 10-times higher than that in the CIN (mean: 0.43). Bcl-2 was expressed 60% of the cases in the dysplastic cells of the CIN II and CIN III, 33.3% of cases in the invasive carcinoma and not expressed in the CIN I except basal cells. The expression of the PCNA was increased by the grades of CIN and was strong in invasive carcinoma.
The mean survival time of the patient with invasive carcinoma was significantly decreased in the higher AI index (above 4.3) than in the lower AI index (below 4.3). There was no significant correlation between the extent of apoptosis and the expression of bcl-2. According to the above results, AI are able to be used as an independent prognostic marker in the invasive cervical carcinoma, and bcl-2 and PCNA have an important role in the tumorigenesis of uterine cervical carcinoma.
This study was carried out to investigate the immunohistochemical expression of bcl-2 and p53 protein in the intestinal type and the diffuse type of gastric adenocarcinoma by Lauren's classification. A total of 100 cases, including 50 cases of the intestinal type and 50 cases of the diffuse type from paraffin embedded gastrectomy specimens, were immunohistochemically stained for bcl-2 and p53 protein. Bcl-2 protein was expressed in 38% (19/50) of intestinal type and 30% (15/50) of diffuse type. The incidence of bcl-2 protein expression was higher in the intestinal type than in the diffuse type, but no significant correlation was present (p>0.05). p53 protein was expressed in 68% (34/50) of the intestinal type and 60% (30/50) of the diffuse type. The incidence of p53 protein expression was higher in the intestinal type than in the diffuse type, but no significant correlation was present (p>0.05). And an expression of bcl-2 and p53 protein did not correlate with depth of invasion, lymph node meatastasis and TNM stage, respectively (p>0.05). These results suggest that bcl-2 and p53 gene alteration appear to play a more important role in the carcinogenesis of the intestinal type than the diffuse type. However, there is no significant difference between the intestinaPU: The Korean Society of Pathologistsl type and the diffuse type in bcl-2 and p53 protein expression.
Taxol is an active chemotherapeutic agent against a variety of solid tumors and a potentially useful drug for augmenting the cytotoxic action of radiotherapy against certain cancers. Taxol blocks cells in the mitotic phase of cell cycle. The aim of this study was to define the in vivo response of rapidly dividing cells of the small intestinal mucosa to taxol. We studied the numbers of apoptotic and mitotic cells and the expression of bcl-2 and p53 in rat jejunal crypt cells at 1, 2, 4, 8, 12, 16, and 24 hours and 3 and 5 days after intraperitoneal injection of taxol.
Mitosis peaked at 2 and 4 hours and 12 and 16 hours.
Apoptosis peaked at 16 hours and returned to normal after five days. The glands in crypts showed marked distortion with atypical lining cells after three days, which returned to normal at 5 days. bcl-2 expression was markedly decreased at 8 to 24 hours and subnormally recovered after three to five days. p53 showed no significant changes throughout. The histopathological changes in small intestine due to taxol were transient with complete recovery. bcl-2 expression was inversely corresponded to numbers of apoptosis. The changes were p53 independent. Further studies to understand the conditions that maximize the cell-cycle modulating effects of taxol cl-may greatly enhance its anti-tumor effectiveness.