© 2013 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12194
APMIS 122: 476–481
Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma OSKAR KOPEREK,1 KLAUS AUMAYR,1 MARTIN SCHINDL,2 GREGOR WERBA,2 AFSCHIN SOLEIMAN,3 SEBASTIAN SCHOPPMANN,2 KLAUS SAHORA2 and PETER BIRNER1 1 Department of Pathology, Medical University of Vienna, Vienna; 2Department of Surgery, Medical University of Vienna, Vienna; and 3Department of Pathology, Laboratory Dr. Soleiman, Hall in Tirol, Austria
Koperek O, Aumayr K, Schindl M, Werba G, Soleiman A, Schoppmann S, Sahora K, Birner P. Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma. APMIS 2014; 122: 476–481. Activation of signal-transcriptional factor signal transducer and activator of transcription 3 (STAT3) is associated with more aggressive behaviour in a variety of human malignancies. As selective STAT3 inhibitors exist, this protein might represent a novel therapeutic target. Although STAT3 seems to play an important role in progression of pancreatic ductal carcinoma (PDAC), only few data on this subject exist. The aim of our study was the investigation of STAT3 activation and its correlation with its possible regulator HER2. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically in 79 PDACs. HER2 status assessed by immunohistochemistry and double colour silver in situ hybridization was available from a previous study. PSTAT3 expression was seen in 33 (41.8%) patients. Six patients were scored as HER2 positive having strong correlation with pSTAT3 expression (p = 0.004, Fisher′s exact test). No association of pSTAT3 expression with patients′ age, tumour staging and grading, perineural invasion of tumour cells or survival time was seen. pSTAT3 is frequently expressed in PDAC. Nevertheless, its immediate clinical relevance seems to be low. However, further research needs to determine whether STAT3 status in PDAC is predictive for the response to novel targeting therapies. Key words: pSTAT3; pancreatic ductal adenocarcinoma; HER2. Klaus Sahora, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18 – 20, Vienna 1090, Austria. e-mail: [email protected]
Signal-transcriptional factor signal transducer and activator of transcription 3(STAT3) is a member of the STAT gene/protein family (1). STAT family members are phosphorylated by receptor-associated kinases and translocate to the nucleus, where they act as transcription factors (2). Signal transducer and activator of transcription 3 has been shown to be frequently overexpressed in a variety of human solid tumours and promoting tumour angiogenesis, suppressing anti-tumour immune response and enhancing tumour progression (3). Signal transducer and activator of transcription 3 might be activated by various mechanisms, among
Received 7 March 2013. Accepted 30 July 2013
476
them cytokines and activation of other membrane tyrosine kinase receptors. In breast cancer cells, it has been shown that STAT3 is a downstream effector of HER2 (4, 5). In addition, the expression of MMP-7 seems to be induced by HER2/STAT3 activation in MCF-7 cells (6). Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death from cancer in the US. Despite combination of radical surgical treatment with adjuvant chemotherapy, the outcome of PDAC is still very poor with an overall 5-year survival of less than 5% (7, 8). Thus, new adjuvant strategies for the treatment of PDAC are urgently required. Signal transducer and activator of transcription 3 has been suggested to play a major role in the pathogenesis of PDAC (9–11).
PSTAT3 IN PANCREATIC DUCTAL CANCER
As STAT3 inhibitors are available, targeting STAT3 might represent a promising novel target in PDAC (12, 13). Surprisingly, only few data on the prognostic relevance of STAT3 activation in PDAC exist so far, having no strong correlation with individual prognosis (14). The aim of our study was to assess the prognostic relevance of STAT3 activation in PDAC. As HER2 is overexpressed also in a subset of PDAC (15), but the correlation between HER2 and STAT3 activation was not yet defined, we wanted to determine the correlation between HER2 expression and STAT3 activation in PDAC. MATERIALS AND METHODS Patients Formalin-fixed, paraffin-embedded tissue from patients who underwent surgical treatment for PDAC between March 1994 and July 2007 were randomly selected from our files. Diagnosis of PDAC was confirmed retrospectively by four experienced surgical pathologists (K.A., A.S., O.K., P.B.).
Methods Immunohistochemistry (IHC) was performed on 3 lm thick histological sections of the paraffin-embedded specimens fixed in 4% buffered formalin. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically with a rabbit monoclonal antibody (clone D3A7, Cell Signalling Technology Inc., Danvers, MA, USA) in a dilution of 1:100 using a Benchmark Ultra immunostainer (Ventana, Tucson, AZ, USA). A sample of oesophageal cancer with known strong pSTAT3 expression served as positive control. For analysis, a specimen was considered as STAT3 negative, if 0.05, Table 1. Clinicopathological data and correlation with pSTAT3 status Clinicopathological data pSTAT3 positive Tumour staging p = 0.595 pT1 (n = 4) 3 (75%) pT2 (n = 25) 9 (36%) pT3 (n = 47) 21 (44.7%) pT4 (n = 3) 0 Lymph node staging p = 0.676 pN0 (n = 26) 10 (38.5%) pN1 (n = 53) 23 (43.4%) Radicality of resection p = 0.04 R0 (n = 51) 17 (33.3%) R1 (n = 28) 16 (57.1%) Histological grading p = 0.888 G1 (n = 8) 4 (50%) G2 (n = 45) 18 (40%) G3 (n = 26) 11 (42.3%) Perineural invasion p = 0.634 No (n = 43) 19 (44.2%) Yes (n = 36) 14 (38.9%) HER2 status* p = 0.003 Negative (n = 73) 27 (37%) Positive (n = 6) 6 (100%) *Significant difference.
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of the included factors showed prognostic relevance for DFS or OS (p > 0.05, Cox regression).
Mann–Whitney U- or Chi-squared tests, as appropriate). A strong correlation of HER2- status with pSTAT3 expression was found (p = 0.004, Fisher′s exact test). While in the 46 tumours without pSTAT3 expression, no tumour scored positive for HER2, all 6 HER2 positive tumours were also positive for pSTAT3 expression (6/33; 18.2%; see Fig. 1). In addition, pSTAT3 expression was associated with subtotal resection (pR1, p = 0.004, Chi-squared test). During a mean observation time of 629 594 (SD) days, 67 (84.8%) patients showed recurrent disease, and 71 patients (89.9%) died. No significant difference in tumour and lymph node stage, radicality of resection, histological grading, patients′ age or presence of perineural invasion (p > 0.05, Mann–Whitney U-test or Chisquared test, respectively; Table 1) was seen between patients with or without pSTAT3 expression in the primary tumour. No association of pSTAT3 expression with DFS (p = 0.2, log-rank test) and OS was observed (p = 0.461, log-rank test). In addition, tumour and lymph node stage, histological grading, perineural invasion or patients′ age also showed no association with DFS or OS (p > 0.05, log-rank test). At multivariate analysis of survival including age, tumour and lymph node staging, histological grading, radicality of resection (total vs subtotal), perineural invasion and pSTAT3 expression, none
DISCUSSION Signal transducer and activator of transcription 3 is involved into physiological cellular response to cytokines and growth factors as transcription factor, and was originally identified as an acute-phase response factor triggered by the epidermal growth factor (EGF) and interleukin-6 (1, 17). After phosphorylation, dimerized STAT3 translocates to the nucleus and regulates there gene transcription (18). Among these identified target genes, bcl-2, cyclin D1, VEGF and MMP2 play an important role in development and progression of malignant tumours (19–21). Thus, it is not surprising that STAT3 is also involved into tumourigenesis, as constitutive activation of STAT3 results in malignant transformation of cell lines and tumour formation when cell lines with activated STAT3 are implanted in nude mice (22). Expression of STAT3 has been shown to be associated with more malignant behaviour of tumour cells and worse prognosis in a variety of human malignancies, e.g. cancers of the breast, prostate, ovary, lung, head and neck, oesophagus and in glioblastoma (23–30). A variety of in vitro data on the role of STAT3 in pancreatic cancer exist:
A
B
C
D
Fig. 1. PSTAT3 and HER2 expression in a case with HER2 amplification. (A) Nuclear pSTAT3 immunohistochemical staining in tumour cells of a ductal pancreatic adenocarcinoma (magnification: 4009); (B) successive section to A with strong membranous immunohistochemical HER2 staining of the tumour cells (magnification: 4009); (C) corresponding overview of the pSTAT3-stained section (magnification: 1009) and (D) corresponding overview of the HER2-stained section (magnification: 1009); the upper left corner was enlarged in A and B respectively.
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PSTAT3 IN PANCREATIC DUCTAL CANCER
In pancreatic cell lines, activated STAT3 leads to overexpression of VEGF, and thus it is suggested to regulate angiogenesis and metastasis in human pancreatic cancer (31). Moreover, in cell culture experiments on pancreatic cancer cell lines, activated STAT3 promotes cellular proliferation by acceleration of G1/S-phase progression (32). Recent studies have shown that inflammatory reactions may play an important role in the pathogenesis of PDAC via activation of STAT3. Obviously, STAT3 activation by IL-6 may promote progression of pancreatic intraepithelial neoplasia and development of pancreas cancer thus linking inflammatory reaction and pancreatic cancer progression (11, 33). In this context, it is of note that STAT3 itself may induce and support a tumourigenic inflammatory microenvironment (34). Thus, it has been suggested that inhibition of STAT3 might represent a potential preventive and therapeutic strategy for pancreatic cancer (35–39). Despite the potential clinical role of STAT3 in PDAC, to our knowledge, only one study investigating this subject exists. Huang et colleagues investigated 71 cancer specimens using immunohistochemistry (14). They observed pSTAT3 expression in 70% of the samples, and it correlated with tumour stage and positive lymph nodes, but not with histological grade. Expression of pSTAT3 was associated with shorter OS, but was of no independent prognostic value in multivariate analysis. In contrast to the findings of Huang et al., we found no association of pSTAT3 expression with tumour or lymph node stage. However, our finding that pSTAT3 expression is not an independent prognostic factor for survival in our cohort is in good correlation with the results of Huang et al., which also observed no independent prognostic relevance (14). It has been shown recently that pancreatic cancer cells promote perineural invasion through STAT3 activation (40). Nevertheless, no association of pSTAT3 expression in tumour cells and perineural invasion was seen in our study, indicating that other mechanisms than STAT3 activation seem to be of more relevance for perineural invasion in PDAC. In vitro studies showed that overexpression of the growth receptor expression ErbB-2 kinase/HER2/ neu leads to a constitutive activation of STAT3 (41–43). In a previous study, we were able to show that STAT3 activation correlates with HER2 status in oesophageal cancer (29). Amplification of HER2 and concomitant protein overexpression is evident in a subset of PDAC. In
© 2013 APMIS. Published by John Wiley & Sons Ltd
our cohort, all 6 PDACs with HER2 amplification were positive for pSTAT3. Thus in PDAC, HER2 overexpression seems to be a stringent upstream regulator of STAT3. In conclusion, our data show that pSTAT3 is frequently expressed in PDAC. However, its clinical relevance seems to be low and it remains questionable if novel therapies targeting STAT3 will be of benefit for PDAC patients.
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of transcription 3 up-regulates vascular endothelial growth factor production and tumor angiogenesis in head and neck squamous cell carcinoma. Oral Oncol 2007;43:785–90. Yakata Y, Nakayama T, Yoshizaki A, Kusaba T, Inoue K, Sekine I. Expression of p-STAT3 in human gastric carcinoma: significant correlation in tumour invasion and prognosis. Int J Oncol 2007;30:437–42. Schoppmann SF, Jesch B, Friedrich J, Jomrich G, Maroske F, Birner P. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. Clin Exp Metastasis 2012;29:615–24. Birner P, Toumangelova-Uzeir K, Natchev S, Guentchev M. STAT3 tyrosine phosphorylation influences survival in glioblastoma. J Neurooncol 2010;100:339–43. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003;22:319–29. Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P, et al. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 2003;125:891–905. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456–69. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9:798–809. Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, Popp FC, et al. Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signaltransducer and activator of transcription 3/hypoxiainducible factor-1alpha autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 2007; 13:6459–68. Huang C, Xie K. Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev 2012;23:25–35. Huang C, Jiang T, Zhu L, Liu J, Cao J, Huang KJ, et al. STAT3-targeting RNA interference inhibits pancreatic cancer angiogenesis in vitro and in vivo. Int J Oncol 2011;38:1637–44. Huang C, Yang G, Jiang T, Cao J, Huang KJ, Qiu ZJ. Down-regulation of STAT3 expression by vectorbased small interfering RNA inhibits pancreatic cancer growth. World J Gastroenterol 2011;17:2992– 3001. Huang C, Yang G, Jiang T, Zhu G, Li H, Qiu Z. The effects and mechanisms of blockage of STAT3 signaling pathway on IL-6 inducing EMT in human pancreatic cancer cells in vitro. Neoplasma 2011;58:396–405. Guo K, Ma Q, Li J, Wang Z, Shan T, Li W, et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the
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activation of STAT3 signaling. Mol Cancer Ther 2013;12:264–73. 41. Hartman ZC, Yang XY, Glass O, Lei G, Osada T, Dave SS, et al. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res 2011;71:4380–91. 42. Fernandes A, Hamburger AW, Gerwin BI. ErbB-2 kinase is required for constitutive stat 3 activation in
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malignant human lung epithelial cells. Int J Cancer 1999;83:564–70. 43. Seo HS, Choi HS, Kim SR, Choi YK, Woo SM, Shin I, et al. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFkappaB signaling in HER2-overexpressing breast cancer cells. Mol Cell Biochem 2012;366:319–34.
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Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma OSKAR KOPEREK,1 KLAUS AUMAYR,1 MARTIN SCHINDL,2 GREGOR WERBA,2 AFSCHIN SOLEIMAN,3 SEBASTIAN SCHOPPMANN,2 KLAUS SAHORA2 and PETER BIRNER1 1 Department of Pathology, Medical University of Vienna, Vienna; 2Department of Surgery, Medical University of Vienna, Vienna; and 3Department of Pathology, Laboratory Dr. Soleiman, Hall in Tirol, Austria
Koperek O, Aumayr K, Schindl M, Werba G, Soleiman A, Schoppmann S, Sahora K, Birner P. Phosphorylation of STAT3 correlates with HER2 status, but not with survival in pancreatic ductal adenocarcinoma. APMIS 2014; 122: 476–481. Activation of signal-transcriptional factor signal transducer and activator of transcription 3 (STAT3) is associated with more aggressive behaviour in a variety of human malignancies. As selective STAT3 inhibitors exist, this protein might represent a novel therapeutic target. Although STAT3 seems to play an important role in progression of pancreatic ductal carcinoma (PDAC), only few data on this subject exist. The aim of our study was the investigation of STAT3 activation and its correlation with its possible regulator HER2. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically in 79 PDACs. HER2 status assessed by immunohistochemistry and double colour silver in situ hybridization was available from a previous study. PSTAT3 expression was seen in 33 (41.8%) patients. Six patients were scored as HER2 positive having strong correlation with pSTAT3 expression (p = 0.004, Fisher′s exact test). No association of pSTAT3 expression with patients′ age, tumour staging and grading, perineural invasion of tumour cells or survival time was seen. pSTAT3 is frequently expressed in PDAC. Nevertheless, its immediate clinical relevance seems to be low. However, further research needs to determine whether STAT3 status in PDAC is predictive for the response to novel targeting therapies. Key words: pSTAT3; pancreatic ductal adenocarcinoma; HER2. Klaus Sahora, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18 – 20, Vienna 1090, Austria. e-mail: [email protected]
Signal-transcriptional factor signal transducer and activator of transcription 3(STAT3) is a member of the STAT gene/protein family (1). STAT family members are phosphorylated by receptor-associated kinases and translocate to the nucleus, where they act as transcription factors (2). Signal transducer and activator of transcription 3 has been shown to be frequently overexpressed in a variety of human solid tumours and promoting tumour angiogenesis, suppressing anti-tumour immune response and enhancing tumour progression (3). Signal transducer and activator of transcription 3 might be activated by various mechanisms, among
Received 7 March 2013. Accepted 30 July 2013
476
them cytokines and activation of other membrane tyrosine kinase receptors. In breast cancer cells, it has been shown that STAT3 is a downstream effector of HER2 (4, 5). In addition, the expression of MMP-7 seems to be induced by HER2/STAT3 activation in MCF-7 cells (6). Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death from cancer in the US. Despite combination of radical surgical treatment with adjuvant chemotherapy, the outcome of PDAC is still very poor with an overall 5-year survival of less than 5% (7, 8). Thus, new adjuvant strategies for the treatment of PDAC are urgently required. Signal transducer and activator of transcription 3 has been suggested to play a major role in the pathogenesis of PDAC (9–11).
PSTAT3 IN PANCREATIC DUCTAL CANCER
As STAT3 inhibitors are available, targeting STAT3 might represent a promising novel target in PDAC (12, 13). Surprisingly, only few data on the prognostic relevance of STAT3 activation in PDAC exist so far, having no strong correlation with individual prognosis (14). The aim of our study was to assess the prognostic relevance of STAT3 activation in PDAC. As HER2 is overexpressed also in a subset of PDAC (15), but the correlation between HER2 and STAT3 activation was not yet defined, we wanted to determine the correlation between HER2 expression and STAT3 activation in PDAC. MATERIALS AND METHODS Patients Formalin-fixed, paraffin-embedded tissue from patients who underwent surgical treatment for PDAC between March 1994 and July 2007 were randomly selected from our files. Diagnosis of PDAC was confirmed retrospectively by four experienced surgical pathologists (K.A., A.S., O.K., P.B.).
Methods Immunohistochemistry (IHC) was performed on 3 lm thick histological sections of the paraffin-embedded specimens fixed in 4% buffered formalin. Expression of tyrosine-705 phosphorylated STAT3 (pSTAT3) was determined immunohistochemically with a rabbit monoclonal antibody (clone D3A7, Cell Signalling Technology Inc., Danvers, MA, USA) in a dilution of 1:100 using a Benchmark Ultra immunostainer (Ventana, Tucson, AZ, USA). A sample of oesophageal cancer with known strong pSTAT3 expression served as positive control. For analysis, a specimen was considered as STAT3 negative, if 0.05, Table 1. Clinicopathological data and correlation with pSTAT3 status Clinicopathological data pSTAT3 positive Tumour staging p = 0.595 pT1 (n = 4) 3 (75%) pT2 (n = 25) 9 (36%) pT3 (n = 47) 21 (44.7%) pT4 (n = 3) 0 Lymph node staging p = 0.676 pN0 (n = 26) 10 (38.5%) pN1 (n = 53) 23 (43.4%) Radicality of resection p = 0.04 R0 (n = 51) 17 (33.3%) R1 (n = 28) 16 (57.1%) Histological grading p = 0.888 G1 (n = 8) 4 (50%) G2 (n = 45) 18 (40%) G3 (n = 26) 11 (42.3%) Perineural invasion p = 0.634 No (n = 43) 19 (44.2%) Yes (n = 36) 14 (38.9%) HER2 status* p = 0.003 Negative (n = 73) 27 (37%) Positive (n = 6) 6 (100%) *Significant difference.
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of the included factors showed prognostic relevance for DFS or OS (p > 0.05, Cox regression).
Mann–Whitney U- or Chi-squared tests, as appropriate). A strong correlation of HER2- status with pSTAT3 expression was found (p = 0.004, Fisher′s exact test). While in the 46 tumours without pSTAT3 expression, no tumour scored positive for HER2, all 6 HER2 positive tumours were also positive for pSTAT3 expression (6/33; 18.2%; see Fig. 1). In addition, pSTAT3 expression was associated with subtotal resection (pR1, p = 0.004, Chi-squared test). During a mean observation time of 629 594 (SD) days, 67 (84.8%) patients showed recurrent disease, and 71 patients (89.9%) died. No significant difference in tumour and lymph node stage, radicality of resection, histological grading, patients′ age or presence of perineural invasion (p > 0.05, Mann–Whitney U-test or Chisquared test, respectively; Table 1) was seen between patients with or without pSTAT3 expression in the primary tumour. No association of pSTAT3 expression with DFS (p = 0.2, log-rank test) and OS was observed (p = 0.461, log-rank test). In addition, tumour and lymph node stage, histological grading, perineural invasion or patients′ age also showed no association with DFS or OS (p > 0.05, log-rank test). At multivariate analysis of survival including age, tumour and lymph node staging, histological grading, radicality of resection (total vs subtotal), perineural invasion and pSTAT3 expression, none
DISCUSSION Signal transducer and activator of transcription 3 is involved into physiological cellular response to cytokines and growth factors as transcription factor, and was originally identified as an acute-phase response factor triggered by the epidermal growth factor (EGF) and interleukin-6 (1, 17). After phosphorylation, dimerized STAT3 translocates to the nucleus and regulates there gene transcription (18). Among these identified target genes, bcl-2, cyclin D1, VEGF and MMP2 play an important role in development and progression of malignant tumours (19–21). Thus, it is not surprising that STAT3 is also involved into tumourigenesis, as constitutive activation of STAT3 results in malignant transformation of cell lines and tumour formation when cell lines with activated STAT3 are implanted in nude mice (22). Expression of STAT3 has been shown to be associated with more malignant behaviour of tumour cells and worse prognosis in a variety of human malignancies, e.g. cancers of the breast, prostate, ovary, lung, head and neck, oesophagus and in glioblastoma (23–30). A variety of in vitro data on the role of STAT3 in pancreatic cancer exist:
A
B
C
D
Fig. 1. PSTAT3 and HER2 expression in a case with HER2 amplification. (A) Nuclear pSTAT3 immunohistochemical staining in tumour cells of a ductal pancreatic adenocarcinoma (magnification: 4009); (B) successive section to A with strong membranous immunohistochemical HER2 staining of the tumour cells (magnification: 4009); (C) corresponding overview of the pSTAT3-stained section (magnification: 1009) and (D) corresponding overview of the HER2-stained section (magnification: 1009); the upper left corner was enlarged in A and B respectively.
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© 2013 APMIS. Published by John Wiley & Sons Ltd
PSTAT3 IN PANCREATIC DUCTAL CANCER
In pancreatic cell lines, activated STAT3 leads to overexpression of VEGF, and thus it is suggested to regulate angiogenesis and metastasis in human pancreatic cancer (31). Moreover, in cell culture experiments on pancreatic cancer cell lines, activated STAT3 promotes cellular proliferation by acceleration of G1/S-phase progression (32). Recent studies have shown that inflammatory reactions may play an important role in the pathogenesis of PDAC via activation of STAT3. Obviously, STAT3 activation by IL-6 may promote progression of pancreatic intraepithelial neoplasia and development of pancreas cancer thus linking inflammatory reaction and pancreatic cancer progression (11, 33). In this context, it is of note that STAT3 itself may induce and support a tumourigenic inflammatory microenvironment (34). Thus, it has been suggested that inhibition of STAT3 might represent a potential preventive and therapeutic strategy for pancreatic cancer (35–39). Despite the potential clinical role of STAT3 in PDAC, to our knowledge, only one study investigating this subject exists. Huang et colleagues investigated 71 cancer specimens using immunohistochemistry (14). They observed pSTAT3 expression in 70% of the samples, and it correlated with tumour stage and positive lymph nodes, but not with histological grade. Expression of pSTAT3 was associated with shorter OS, but was of no independent prognostic value in multivariate analysis. In contrast to the findings of Huang et al., we found no association of pSTAT3 expression with tumour or lymph node stage. However, our finding that pSTAT3 expression is not an independent prognostic factor for survival in our cohort is in good correlation with the results of Huang et al., which also observed no independent prognostic relevance (14). It has been shown recently that pancreatic cancer cells promote perineural invasion through STAT3 activation (40). Nevertheless, no association of pSTAT3 expression in tumour cells and perineural invasion was seen in our study, indicating that other mechanisms than STAT3 activation seem to be of more relevance for perineural invasion in PDAC. In vitro studies showed that overexpression of the growth receptor expression ErbB-2 kinase/HER2/ neu leads to a constitutive activation of STAT3 (41–43). In a previous study, we were able to show that STAT3 activation correlates with HER2 status in oesophageal cancer (29). Amplification of HER2 and concomitant protein overexpression is evident in a subset of PDAC. In
© 2013 APMIS. Published by John Wiley & Sons Ltd
our cohort, all 6 PDACs with HER2 amplification were positive for pSTAT3. Thus in PDAC, HER2 overexpression seems to be a stringent upstream regulator of STAT3. In conclusion, our data show that pSTAT3 is frequently expressed in PDAC. However, its clinical relevance seems to be low and it remains questionable if novel therapies targeting STAT3 will be of benefit for PDAC patients.
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