Lectin histochemistry of resected adenocarcinoma of the lung: helix pomatia agglutinin binding is an independent prognostic factor

The worldwide incidence of adenocarcinoma of the lung is rising. Unfortunately, no significant prognostic marker beyond the classical TNM staging exists to stratify these patients for appropriate therapy. Because lectins, carbohydrate-binding proteins, have been shown to be useful prognostic markers in several other adenocarcinomas, a panel of lectins [Helix pomatia agglutinin (HPA), Phaseolus vulgaris leukoagglutinin, Ulex europaeus agglutinin, Maackia amurenis agglutinin, Sambucus nigra agglutinin] with different carbohydrate-binding specificities were tested for their prognostic relevance. Paraffin wax sections of 93 patients with adenocarcinomas of the lung who had undergone surgery between 1990 and 1995 were investigated by lectin histochemistry. Lectin-binding data and other known prognostic factors were correlated with survival. In univariate analysis, binding of HPA, Phaseolus vulgaris leukoagglutinin, and Ulex europaeus agglutinin to adenocarcinoma cells were prognostic indicators for overall and relapse-free survival, whereas Maackia amurenis agglutinin and Sambucus nigra agglutinin binding had no prognostic value. However, in a multivariate analysis next to stage and gender only HPA was a significant independent prognostic factor on survival. In conclusion, HPA binding was the primary marker-based predictor of prognosis in our patient population and allows to stratify patients with adenocarcinomas of the lung into a low- and a high-risk group.     

UCH-LI acts as a novel prognostic biomarker in gastric cardiac adenocarcinoma

Gastric cardiac adenocarcinoma (GCA) accounts for a majority of gastric cancer population and harbors unfavorable outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) belongs to the deubiquitinating enzyme family, which could regulate cell growth in human cancers. In the present study, expression of UCH-L1 was evaluated in 196 GCAs by immunohistochemistry using tissue microarray and its function on gastric cancer cells was measured. UCH-L1 expression was increased in GCA specimens, compared with their normal tissues and UCH-L1 overexpression is tightly correlated with tumor size and overall TNM stage. Log-rank analysis showed that UCH-L1 positive is reversely associated with cumulative survival (P<0.001). Multivariate Cox regression model showed that UCH-L1 overexpression is a remarkably negative predictor in GCA prognosis (Hazard Ratio=0.53, P<0.01), along with advanced TNM stage that is a known negative factor in gastric cancers (Hazard Ratio=0.33, P<0.05). Silencing of UCH-L1 reduced the ability of cell proliferation, colony formation, migration and invasion of gastric cancer cells. Our findings suggest that UCH-L1 is a promising prognostic biomarker for GCAs and might play an important role in the carcinogenesis of gastric cancer.     

Overexpression of YKL-40 is an independent prognostic marker in gastric cancer

YKL-40 is a growth factor for connective tissue cells and a migration factor for endothelial cells. Elevated serum level of YKL-40 has been associated with poor prognosis in many cancers. However, the status of YKL-40 expression and its clinical/prognostic significance in gastric cancer are unclear. In this study, the expression of YKL-40 was studied by immunohistochemistry in gastric cancer tissue microarray containing 172 primary gastric cancer cases and 70 adjacent nonneoplastic mucosa specimens. The correlations between YKL-40 expression and clinicopathologic features, as well as activation of PI3K/Akt pathways were addressed. Expression of YKL-40 was significantly higher in gastric cancer tissues than that in adjacent nonneoplastic tissues. Overexpression YKL-40 was found in 28.4% of gastric cancers and was significantly associated with tumor invasion (P = .007) and lymph node metastasis (P = .009). For survival study, overexpression of YKL-40 was significantly associated with worse outcome (P = .001). When known clinical variables were added to a multivariate analysis, TNM stage, tumor size, and overexpression of YKL-40 emerged as independent prognostic factors. Further study indicated that the oncogenic function of YKL-40 might be through the activation of Akt pathway. These results suggest that overexpression of YKL-40 is correlated with the aggressive behavior of tumor cells, which could be used as an independent molecular marker for the predicting poor prognosis of patients with gastric cancer.     

CD51 is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma

Background

Esophageal squamous cell carcinoma (ESCC) is a common cancer in East Asia and some other parts of the world with a dismal prognosis. CD51 (integrin αv),a transmembrane glycoprotein responsible for cell-to-matrix binding has been found to enhance tumor progression. However, its expression and clinicopathological significance in ESCC tumors are not fully understood. The purpose of this study was to investigate the expression level of CD51 and to explore its clinicopathological significance in ESCC.

Sineoculis homeobox homolog 1 protein overexpression as an independent biomarker for pancreatic ductal adenocarcinoma

Sineoculis homeobox homolog 1 (SIX1) is a member of the SIX gene family. It is highly expressed in cancers derived from tissues that play a fundamental role during embryogenesis. Recent studies suggest that inappropriate expression of SIX1 can both initiate tumorigenesis and promote metastasis. To investigate the clinicopathological significance of SIX1 expression in pancreatic ductal adenocarcinoma (PDAC), and to further identify its role as a potential biomarker and therapeutic target in PDAC, 103 PDAC tissue samples and 45 normal pancreatic tissue samples were immunohistochemically stained for SIX1 protein. The localization of SIX1 protein was detected in Panc-1 cancer cells using immunofluorescence staining. Correlations between SIX1 overexpression and the clinicopathological features of pancreatic cancer were evaluated using Chi-square (χ²) tests, differences in survival curves were analyzed using log-rank tests, and multivariate survival analysis was performed using the Cox proportional hazard regression model. In results, SIX1 protein showed mainly cytoplasmic/perinuclear staining pattern in PDAC with immunohistochemistry. The strongly positive rate of SIX1 protein was 60.2% (62/103) in PDAC, which was significantly higher than normal pancreatic tissue (6.7%, 3/45). SIX1 overexpression was positively correlated with tumor size, TNM stage, lymph node metastasis, and grade of PDAC (P < 0.001). SIX1 high expression levels influenced overall survival rates in G1, G2, stage I–II and stage III–IV groups of PDAC; and high expression levels had significantly lower overall survival rates than SIX1 low expression levels. In conclusion, SIX1 emerged as a significant independent prognostic factor in PDAC. SIX1 overexpression appears to be associated with PDAC, and may be a potential biomarker for early diagnosis and prognostic evaluation of PDAC.     

Monocarboxylate Transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancer

Background

Endometrial cancer (EC) is a major health concern due to its rising incidence. Whilst early stage disease is generally cured by surgery, advanced EC has a poor prognosis with limited treatment options. Altered energy metabolism is a hallmark of malignancy. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain intracellular pH. The aim of this study was to evaluate the expression of the lactate/proton monocarboxylate transporters MCT1 and MCT4 and their chaperone CD147 in EC, with the ultimate aim of directing future drug development.

Methods

MCT1, MCT4 and CD147 expression was examined using immunohistochemical analysis in 90 endometrial tumours and correlated with clinico-pathological characteristics and survival outcomes.

Results

MCT1 and MCT4 expression was observed in the cytoplasm, the plasma membrane or both locations. CD147 was detected in the plasma membrane and associated with MCT1 (p =?0.003) but not with MCT4 (p =?0.207) expression. High MCT1 expression was associated with reduced overall survival (p =?0.029) and remained statistically significant after adjustment for survival covariates (p =?0.017).

Conclusion

Our data suggest that MCT1 expression is an important marker of poor prognosis in EC. MCT1 inhibition may have potential as a treatment for advanced or recurrent EC.

     

Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma

Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme in prostanoid biosynthesis and is involved in tumor progression. We investigated expression of COX-1 and COX-2 in cell lines and tumors from ovarian carcinomas. Expression of COX-2 mRNA and protein was detectable in three of five ovarian carcinoma cell lines and was inducible by interleukin-1beta or phorbolester in a subset of cell lines. Prostaglandin E(2) (PGE(2)) production could be inhibited by the selective COX-2 inhibitor NS-398. In malignant ascites of ovarian carcinomas significantly increased levels of PGE(2) were found compared to other carcinomas or nonmalignant ascites (P = 0.03). We investigated expression of COX-2 by immunohistochemistry in 117 ovarian surface epithelial tumors. Expression of COX-2 was detected in 42% of 86 ovarian carcinomas and in 37% of 19 low malignant potential tumors, but not in 12 cystadenomas or 2 normal ovaries. Expression of COX-1 was detected by immunohistochemistry in 75% of 75 invasive ovarian carcinomas and in 75% of 16 low malignant potential tumors, whereas 2 samples from normal ovaries and 8 cystadenomas were positive for COX-1. In univariate survival analysis of invasive carcinomas, expression of COX-2 was associated with a significantly reduced median survival time (log rank test, P = 0.04). For patients younger than 60 years of age, this association was even more significant (P < 0.004). In contrast, expression of COX-1 was no prognostic parameter (P = 0.89). There was no significant correlation between COX-2 or COX-1 expression and other clinicopathological markers. In multivariate analysis expression of COX-2 was an independent prognostic factor for poor survival (relative risk, 2.74; 95% CI, 1.38 to 5.47). Our data indicate that COX-2 expression is an independent prognostic factor in ovarian carcinoma. Based on the results of this study, it would be interesting to investigate whether ovarian carcinoma patients with tumors positive for COX-2 would benefit from treatment with selective COX-2 inhibitors.     

Expression of Beclin-1, an autophagy-related protein,is associated with tumoral FOXP3 expression and Tregs in gastric adenocarcinoma: The function of Beclin-1 expression as a favorable prognostic factor in gastric adenocarcinoma

BackgroundAutophagy, which is stimulated by cellular or environmental stresses, is involved in several distinct biological processes, and the regulation mechanism is complex. Autophagy has been reported to modulate immune system components. In the present study, the expression of Beclin-1 and LC3, an autophagy-related proteins, and its relationship with FOXP3 expression were investigated in gastric adenocarcinoma cells and FOXP3+T cells (regulatory T cells).MethodsTissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected at Kyung Hee University Hospital at Gangdong from 2006 to 2012. Immunohistochemical staining for Beclin-1, LC3, FOXP3, and CD8 was performed.ResultsConsequently, positive Beclin-1 expression was significantly associated with a smaller tumor size, mixed histologic type, better histologic grade, lower T category, lower N category, lower recurrence rate, less lymphatic invasion, less vascular invasion, and less neural invasion. Positive tumoral FOXP3 expression was significantly associated with a lower T category, lower N category, lower recurrence rate, and less lymphatic invasion. The cases of more infiltrated Tregs (≥ 25/high power field, HPF) significantly correlated with a lower N category, lower recurrence rate, less lymphatic invasion, more infiltrated CD8+T cells, and a higher number of tumor-infiltrating lymphocytes. Beclin-1 and LC3 expression were positively correlated with tumoral FOXP3 overexpression. In addition, Beclin-1 expression was significantly associated with a greater number of infiltrated Tregs in gastric adenocarcinoma. Both the positive Beclin-1 expression and positive tumoral FOXP3 expression cases showed significantly better disease-free and overall survival. In addition, the patients with an increased number of infiltrated Tregs (≥ 25/HPF) showed better disease-free and overall survival rates.ConclusionIn conclusion, the autophagic function of Beclin-1 in gastric adenocarcinoma cells was associated with an increased number of infiltrated Tregs and tumoral FOXP3 containing tumor suppressor function. Therefore, the favorable effects of Beclin-1 expression in gastric adenocarcinoma is associated with the regulation of Tregs and tumoral FOXP3 expression.     

Preoperative serum CA19-9 levels is an independent prognostic factor in patients with resected hilar cholangiocarcinoma

To investigate the appropriate cutoff point of CA19-9 for prognosis and other potential prognostic factors that may affect survival of patients with hilar cholangiocarcinoma (HC) after radical surgery. 168 patients who had undergone radical surgery for hilar cholangiocarcinoma and resultant macroscopic curative resection (R0 and R1) were discreetly selected for analyses. Categorized versions were used in univariate model to determine the appropriate cutoff point of CA19-9. CA19-9 and other clinicopathologic factors were analyzed for influence on survival by univariate and multivariate methods. The strongest univariate predictor among the categorized preoperative CA19-9 measures was CA19-9 less than 150 IU/L (P = 0.000). In univariate analysis, tumor size, Bismuth-Corlette classification, portal vein invasion, Lymph node metastasis, resection margin and preoperative CA19-9 levels were identified as significant prognostic factors. In multivariable analysis, lymph node metastasis, resection margin and preoperative CA19-9 levels were independent prognostic factors. our results demonstrated that preoperative CA19-9 levels was also an independent prognostic factor for hilar cholangiocarcinoma, and the most discriminative cutoff point of CA19-9 for prognosis proved to be at 150 U/ml.     

Survivin expression is an independent poor prognostic marker in lung adenocarcinoma but not in squamous cell carcinoma

Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn’t find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p?=?0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p?=?0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p?=?0.837, OS; 61.0 vs. 62.4 months; p?=?0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123–2.532; p?=?0.012; OS: HR, 1.965; 95 % CI, 1.108–3.486; p?=?0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p?>?0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.     

Lin28B is a novel prognostic marker in gastric adenocarcinoma

Lin28B, a homologue of Lin28, represses biogenesis of let-7 microRNAs with a role in tumorigenesis and is considered a potential therapeutic target for various human cancers. The aim of the study was to identify the clinical significance of Lin28B in gastric adenocarcinoma (GAC). We examined the expression of Lin28B in 97 human gastric cancer samples with 32 samples of non-dysplastic tissues by immunohistochemistry. In the 97 GAC cases, 42 were with high Lin28B expression. The expression levels of Lin28B proteins in GAC were higher than in corresponding adjacent normal tissues (P=0.001). Significant correlations were noted between Lin28B expression and lymph node status (P=0.005), TNM stage (P < 0.001), tumor invasion (P=0.036), and differentiation (P=0.001) of GAC patients. The Kaplan-Meier estimates showed a negative correlation of overall 5-year survival rate with Lin28B expression where higher expression resulted in poorer prognosis in GAC. In univariate analysis, lymph node metastasis, TNM stage, serosal invasion, Lin28B expression as well as differentiation grade could predict the prognosis of GAC patients (P=0.002, P < 0.001, P=0.003, P < 0.001, P=0.001, respectively). Multivariate analysis revealed that the expression level of Lin28B (P < 0.001), TNM stage (P < 0.001) as well as differentiation grade (P < 0.001) were the three potential independent prognostic factors in our study [Hazard ratio (HR)=2.108 and P=0.017, HR=1.994 and P=0.018, HR=1.939 and P=0.046, respectively]. Our findings point to the prognostic role of Lin28B in GAC, and indicate Lin28B as a potential therapeutic target of GAC patients.     

BDNF is a prognostic biomarker involved in immune infiltration of lung adenocarcinoma and is associated with brain metastasis

Non-small cell lung cancer (NSCLC) is one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies, particularly lung adenocarcinoma (LUAD). Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to several human malignancies and has been shown to promote LUAD tumorigenesis. However, its function in the tumour immune microenvironment (TIME) remains largely unexplored, especially in complex brain tissue environments. In this study, BDNF was found to be particularly increased in patients with advanced tumour stage, lymphatic metastasis, and distant metastasis, indicating a correlation with LUAD progression. We characterized the prognostic value of BDNF and defined BDNF as an unfavourable prognostic indicator through a common driver gene-independent mechanism in LUAD. Furthermore, patients with increased BDNF levels in primary LUAD might have a higher risk of developing brain metastasis (BM), and central nervous system (CNS) metastasis showed an elevated expression of BDNF compared to their matched primary lesions. Additionally, we investigated the interaction between BDNF and infiltrating immune cells in both primary lesions and paired BM using multiplex immunostaining. The results showed that BDNF might drive an immunosuppressive tumour microenvironment (TME) by re-education of tumour-associated macrophages (TAMs) toward a pro-tumorigenic M2 phenotype, particularly in BM. Our findings demonstrate that BDNF serves as an independent potential prognostic marker and correlates with BM in LUAD. As it is closely related to TAM polarization, BDNF may be a promising immune-related biomarker and molecular target in patients with LUAD.     

Spindle proteins in resected pancreatic head adenocarcinomas: BubR1 is an independent prognostic factor in pancreatobiliary‐type tumours

Gladhaug I P, Westgaard A, Schjølberg A R, Burum‐Auensen E, Pomianowska E & Clausen O P F
(2010) Histopathology 56, 345–355 Spindle proteins in resected pancreatic head adenocarcinomas: BubR1 is an independent prognostic factor in pancreatobiliary‐type tumours Aims: Spindle proteins such as Aurora A, Mad2 and BubR1 are important for chromosome segregation during mitosis. Dysfunction of these proteins is implicated in the development of many cancers. The aim was to examine their possible prognostic impact in resected adenocarcinomas in the pancreatic head. Methods and results: Two hundred and eighteen consecutively resected pancreatobiliary‐type (n = 145) and intestinal‐type (n = 73) adenocarcinomas involving the pancreatic head were examined for expression of Aurora A, Mad2 and BubR1 by immunohistochemistry on tissue microarrays. Aurora A (P < 0.001) and Mad2 (P = 0.003) were expressed more often and at higher levels in intestinal‐type compared with pancreatobiliary‐type tumours, whereas BubR1 was equally expressed in both histological types. Expression of BubR1, Aurora A and Mad2 was not associated with ploidy status. None of the spindle proteins was significantly associated with prognosis in intestinal‐type tumours. In pancreatobiliary‐type tumours, any BubR1 expression was sufficient to predict poor prognosis (P = 0.006), whereas Aurora A and Mad2 expression was not significantly associated with prognosis (P = 0.86 and P = 0.87, respectively). On adjusted Cox regression analysis, BubR1 expression independently predicted poor prognosis [P =0.002; hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.26, 2.79)], particularly in small tumours (P = 0.001; HR 2.93, 95% CI 1.53, 5.62). Conclusion: BubR1 expression is a novel, independent adverse prognostic factor after pancreatoduodenectomy of pancreatobiliary‐type adenocarcinomas.     

Rictor is an independent prognostic factor for endometrial carcinoma

Early-stage endometrial carcinoma (EC) patients have a high cure rate; however, those with high-risk factors may have poor prognosis. Thus, there is an urgent need for searching for new prognostic molecules to more accurately predict survival of patients. We detected the Rictor mRNA expression level in 30 fresh EC tissue and 17 normal endometrial tissue samples with real-time quantitative RT-PCR and Rictor protein expression level in 134 (test cohort) and 115 (validation cohort) paraffin tissue samples by immunohistochemistry, analyzed the correlation between variables and overall survival (OS) using Cox proportional hazards regression, compared the prognostic accuracy of Rictor with other clinicopathological risk factors by logistic regression. The results showed that Rictor mRNA expression of EC is higher than that of normal endometrium; Rictor protein expression level was closely correlated with FIGO stage, grade and vascular invasion in both cohorts; a univariate analysis showed that the pathological type, stage, grade, vascular invasion, lymphatic metastasis and Rictor were predictors of OS in both cohorts; furthermore, multivariate Cox proportional hazards regression analysis indicated that vascular invasion and Rictor were independent prognostic factors for EC in both cohorts; an ROX curve comparison showed that the area under the curve (AUC) for Rictor combined with other clinicopathological prognostic factors was higher than any individual factor or other clinicopathological prognostic factors’ combination. Based on the above data, we concluded that Rictor is an independent prognostic factor for EC. It combined with other clinicopathological risk factors was a stronger prognostic model than individual risk factor or their combination.