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STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, Marié IJ, Hassler MR, Javaheri T, Aksoy O, Blayney JK, Prutsch N, Skucha A, Herac M, Krämer OH, Mazal P, Grebien F, Egger G, Poli V, Mikulits W, Eferl R, Esterbauer H, Kennedy R, Fend F, Scharpf M, Braun M, Perner S, Levy DE, Malcolm T, Turner SD, Haitel A, Susani M, Moazzami A, Rose-John S, Aberger F, Merkel O, Moriggl R, Culig Z, Dolznig H, Kenner L - Nat Commun (2015)

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

ABSTRACT
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

No MeSH data available.


Related in: MedlinePlus

Co-deletion of Stat3 and Pten enhances prostate cancer transformation and metastatic potential.(a) Histopathological analysis of primary PCa, livers and lungs at 52 weeks of age from WT, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. The dashed red lines encircle areas of advanced liver or lung metastases (M), which are surrounded by normal liver (Li) or normal lung (Lu), respectively. Scale bars, 100 μm; insets: × 600 magnification. (b) Percentage of mice with sites of distant PCa metastases (n=49). (c) Summary of the histological findings of mouse prostates examined at 19 weeks postpartum (p.p.) from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. (d) Summary of the histological findings of mouse prostates examined at 52 weeks p.p. from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. Histological grading and classification of mouse prostates was done according to Chen et al.67 (e) Stat3 IHC in 19-week- and 52-week-old Ptenpc−/− prostate tumours. Scale bars, 100 μm. (f) Quantification of Stat3 staining in 19-week- and 52-week-old Ptenpc−/− prostate tumours using HistoQuest software, P<0.0001. Data were analysed by Student's t-test and are shown as mean±s.d. (n=5).
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f2: Co-deletion of Stat3 and Pten enhances prostate cancer transformation and metastatic potential.(a) Histopathological analysis of primary PCa, livers and lungs at 52 weeks of age from WT, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. The dashed red lines encircle areas of advanced liver or lung metastases (M), which are surrounded by normal liver (Li) or normal lung (Lu), respectively. Scale bars, 100 μm; insets: × 600 magnification. (b) Percentage of mice with sites of distant PCa metastases (n=49). (c) Summary of the histological findings of mouse prostates examined at 19 weeks postpartum (p.p.) from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. (d) Summary of the histological findings of mouse prostates examined at 52 weeks p.p. from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. Histological grading and classification of mouse prostates was done according to Chen et al.67 (e) Stat3 IHC in 19-week- and 52-week-old Ptenpc−/− prostate tumours. Scale bars, 100 μm. (f) Quantification of Stat3 staining in 19-week- and 52-week-old Ptenpc−/− prostate tumours using HistoQuest software, P<0.0001. Data were analysed by Student's t-test and are shown as mean±s.d. (n=5).

Mentions: Compared with Ptenpc−/− mice16, Ptenpc−/−Stat3pc−/− mice displayed a significantly reduced median survival (Fig. 1g). Intriguingly, Ptenpc−/−Stat3pc−/− mice developed high-grade (poorly differentiated) PCa with liver and lung metastases (Fig. 2a). Histopathological analysis of PCa-bearing animals revealed widespread metastasis in 75% of Ptenpc−/−Stat3pc−/− mice. By contrast, Ptenpc−/− mice only showed local invasion into seminal vesicles and never developed distant metastases (Fig. 2b and Supplementary Table 1). Furthermore, loss of Stat3 promoted PCa formation in Pten heterozygous prostate tissue (Ptenpc+/−Stat3pc−/−) at 19 weeks of age, whereas Ptenpc+/−mice developed only prostatic intraepithelial neoplasia17 (PIN) (Supplementary Fig. 3a). Our data demonstrate that Stat3 suppresses malignant progression of Pten-deficient PCa. We found reduced p53 protein expression in Ptenpc+/−Stat3pc−/− prostates (Supplementary Fig. 3b). Pten heterozygosity alone had no effect on p53 expression as demonstrated before11. Interestingly, prostate-specific loss of Stat3 (Stat3pc−/−) led to development of PIN lesions in prostates at 19 weeks of age (Supplementary Fig. 3c). Analysis of consecutive sections revealed invasive regions and high-grade PIN in Ptenpc−/− mice at 19 weeks of age, whereas Ptenpc−/−Stat3pc−/− mice showed early progression to poorly differentiated adenocarcinoma (Fig. 2c). At 52 weeks of age Ptenpc−/−Stat3pc−/− tumours had developed into poorly differentiated carcinomas with 86% penetrance compared with Ptenpc−/− tumours, which showed only signs of focal invasion and late adenocarcinoma formation (Fig. 2d). Notably, Ptenpc−/− tumour cells uniformly expressed nuclear Stat3 at 19 weeks of age (Fig. 2e), whereas more advanced tumours at 52 weeks of age showed profoundly reduced nuclear Stat3 expression (Fig. 2e,f), suggesting that Stat3 expression decreased during PCa progression.


STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, Marié IJ, Hassler MR, Javaheri T, Aksoy O, Blayney JK, Prutsch N, Skucha A, Herac M, Krämer OH, Mazal P, Grebien F, Egger G, Poli V, Mikulits W, Eferl R, Esterbauer H, Kennedy R, Fend F, Scharpf M, Braun M, Perner S, Levy DE, Malcolm T, Turner SD, Haitel A, Susani M, Moazzami A, Rose-John S, Aberger F, Merkel O, Moriggl R, Culig Z, Dolznig H, Kenner L - Nat Commun (2015)

Co-deletion of Stat3 and Pten enhances prostate cancer transformation and metastatic potential.(a) Histopathological analysis of primary PCa, livers and lungs at 52 weeks of age from WT, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. The dashed red lines encircle areas of advanced liver or lung metastases (M), which are surrounded by normal liver (Li) or normal lung (Lu), respectively. Scale bars, 100 μm; insets: × 600 magnification. (b) Percentage of mice with sites of distant PCa metastases (n=49). (c) Summary of the histological findings of mouse prostates examined at 19 weeks postpartum (p.p.) from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. (d) Summary of the histological findings of mouse prostates examined at 52 weeks p.p. from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. Histological grading and classification of mouse prostates was done according to Chen et al.67 (e) Stat3 IHC in 19-week- and 52-week-old Ptenpc−/− prostate tumours. Scale bars, 100 μm. (f) Quantification of Stat3 staining in 19-week- and 52-week-old Ptenpc−/− prostate tumours using HistoQuest software, P<0.0001. Data were analysed by Student's t-test and are shown as mean±s.d. (n=5).
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f2: Co-deletion of Stat3 and Pten enhances prostate cancer transformation and metastatic potential.(a) Histopathological analysis of primary PCa, livers and lungs at 52 weeks of age from WT, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. The dashed red lines encircle areas of advanced liver or lung metastases (M), which are surrounded by normal liver (Li) or normal lung (Lu), respectively. Scale bars, 100 μm; insets: × 600 magnification. (b) Percentage of mice with sites of distant PCa metastases (n=49). (c) Summary of the histological findings of mouse prostates examined at 19 weeks postpartum (p.p.) from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. (d) Summary of the histological findings of mouse prostates examined at 52 weeks p.p. from WT, Stat3pc−/−, Ptenpc−/− and Ptenpc−/−Stat3pc−/− mice. Histological grading and classification of mouse prostates was done according to Chen et al.67 (e) Stat3 IHC in 19-week- and 52-week-old Ptenpc−/− prostate tumours. Scale bars, 100 μm. (f) Quantification of Stat3 staining in 19-week- and 52-week-old Ptenpc−/− prostate tumours using HistoQuest software, P<0.0001. Data were analysed by Student's t-test and are shown as mean±s.d. (n=5).
Mentions: Compared with Ptenpc−/− mice16, Ptenpc−/−Stat3pc−/− mice displayed a significantly reduced median survival (Fig. 1g). Intriguingly, Ptenpc−/−Stat3pc−/− mice developed high-grade (poorly differentiated) PCa with liver and lung metastases (Fig. 2a). Histopathological analysis of PCa-bearing animals revealed widespread metastasis in 75% of Ptenpc−/−Stat3pc−/− mice. By contrast, Ptenpc−/− mice only showed local invasion into seminal vesicles and never developed distant metastases (Fig. 2b and Supplementary Table 1). Furthermore, loss of Stat3 promoted PCa formation in Pten heterozygous prostate tissue (Ptenpc+/−Stat3pc−/−) at 19 weeks of age, whereas Ptenpc+/−mice developed only prostatic intraepithelial neoplasia17 (PIN) (Supplementary Fig. 3a). Our data demonstrate that Stat3 suppresses malignant progression of Pten-deficient PCa. We found reduced p53 protein expression in Ptenpc+/−Stat3pc−/− prostates (Supplementary Fig. 3b). Pten heterozygosity alone had no effect on p53 expression as demonstrated before11. Interestingly, prostate-specific loss of Stat3 (Stat3pc−/−) led to development of PIN lesions in prostates at 19 weeks of age (Supplementary Fig. 3c). Analysis of consecutive sections revealed invasive regions and high-grade PIN in Ptenpc−/− mice at 19 weeks of age, whereas Ptenpc−/−Stat3pc−/− mice showed early progression to poorly differentiated adenocarcinoma (Fig. 2c). At 52 weeks of age Ptenpc−/−Stat3pc−/− tumours had developed into poorly differentiated carcinomas with 86% penetrance compared with Ptenpc−/− tumours, which showed only signs of focal invasion and late adenocarcinoma formation (Fig. 2d). Notably, Ptenpc−/− tumour cells uniformly expressed nuclear Stat3 at 19 weeks of age (Fig. 2e), whereas more advanced tumours at 52 weeks of age showed profoundly reduced nuclear Stat3 expression (Fig. 2e,f), suggesting that Stat3 expression decreased during PCa progression.

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

ABSTRACT
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

No MeSH data available.


Related in: MedlinePlus