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Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas.

Slotta-Huspenina J, Berg D, Bauer K, Wolff C, Malinowsky K, Bauer L, Drecoll E, Bettstetter M, Feith M, Walch A, Höfler H, Becker KF, Langer R - PLoS ONE (2012)

Bottom Line: The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029).In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA.Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Technische Universität München, Munich, Germany. slotta.huspenina@lrz.tum.de

ABSTRACT
A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

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Survival analysis for oesophageal adenocarcinoma patients.Kaplan-Meier survival curves for 82 patients from Clusters A and B with respect to overall survival (A) and disease-free survival (B). Patients who died within the first month after surgery (N = 5) were excluded from the survival analysis.
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pone-0041420-g003: Survival analysis for oesophageal adenocarcinoma patients.Kaplan-Meier survival curves for 82 patients from Clusters A and B with respect to overall survival (A) and disease-free survival (B). Patients who died within the first month after surgery (N = 5) were excluded from the survival analysis.

Mentions: To further assess the relevance of the specific HSP and GRP protein expression patterns identified, we compared the pathological features and the clinical outcome of the different patient groups. Patients from Cluster B were more likely to have lymph node metastases, although this difference was not statistically significant (p = 0.073). For the other factors (pT category, distant metastases, and tumour differentiation), no correlation was found. According to the criteria given above, survival analysis was conducted for 82 patients. Interestingly, the survival analysis showed a better prognosis for patients from Cluster A (n = 32) compared to patients from Cluster B (n = 50), with a prolonged overall survival (median OS 87 months; 95% CI = 59–114 months vs. 28 months; 95% CI = 16–40 months; p = 0.015; Figure 3A) and a significantly prolonged disease-free survival (median DFS 87 months; 95% CI = 30–143 months vs. 25 months; 95% CI = 9–40 months; p = 0.010; Figure 3B). Other factors that showed significant prognostic value in univariate analysis were: UICC pT category (OS: p<0.001; DFS: p = 0.001), presence/absence of lymph node metastases (SO and DFS: p<0.001), presence/absence of distant metastases (OS and DFS: p = 0.001), complete/incomplete tumour resection (OS: p = 0.001; DFS: p = 0.002). Multivariate analysis including UICC pT and pN category, tumour grading, and the clustered protein expression pattern showed that protein expression was the best independent prognostic indicator for overall (p = 0.029) and disease-free survival (p = 0.012) besides lymph node status (p = 0.004 and p = 0.010, respectively) (Tables 3and4).


Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas.

Slotta-Huspenina J, Berg D, Bauer K, Wolff C, Malinowsky K, Bauer L, Drecoll E, Bettstetter M, Feith M, Walch A, Höfler H, Becker KF, Langer R - PLoS ONE (2012)

Survival analysis for oesophageal adenocarcinoma patients.Kaplan-Meier survival curves for 82 patients from Clusters A and B with respect to overall survival (A) and disease-free survival (B). Patients who died within the first month after surgery (N = 5) were excluded from the survival analysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404067&req=5

pone-0041420-g003: Survival analysis for oesophageal adenocarcinoma patients.Kaplan-Meier survival curves for 82 patients from Clusters A and B with respect to overall survival (A) and disease-free survival (B). Patients who died within the first month after surgery (N = 5) were excluded from the survival analysis.
Mentions: To further assess the relevance of the specific HSP and GRP protein expression patterns identified, we compared the pathological features and the clinical outcome of the different patient groups. Patients from Cluster B were more likely to have lymph node metastases, although this difference was not statistically significant (p = 0.073). For the other factors (pT category, distant metastases, and tumour differentiation), no correlation was found. According to the criteria given above, survival analysis was conducted for 82 patients. Interestingly, the survival analysis showed a better prognosis for patients from Cluster A (n = 32) compared to patients from Cluster B (n = 50), with a prolonged overall survival (median OS 87 months; 95% CI = 59–114 months vs. 28 months; 95% CI = 16–40 months; p = 0.015; Figure 3A) and a significantly prolonged disease-free survival (median DFS 87 months; 95% CI = 30–143 months vs. 25 months; 95% CI = 9–40 months; p = 0.010; Figure 3B). Other factors that showed significant prognostic value in univariate analysis were: UICC pT category (OS: p<0.001; DFS: p = 0.001), presence/absence of lymph node metastases (SO and DFS: p<0.001), presence/absence of distant metastases (OS and DFS: p = 0.001), complete/incomplete tumour resection (OS: p = 0.001; DFS: p = 0.002). Multivariate analysis including UICC pT and pN category, tumour grading, and the clustered protein expression pattern showed that protein expression was the best independent prognostic indicator for overall (p = 0.029) and disease-free survival (p = 0.012) besides lymph node status (p = 0.004 and p = 0.010, respectively) (Tables 3and4).

Bottom Line: The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029).In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA.Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Technische Universität München, Munich, Germany. slotta.huspenina@lrz.tum.de

ABSTRACT
A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

Show MeSH
Related in: MedlinePlus