Limits...
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

Deletion of IL-6 and Pten triggers progressive prostate tumorigenesis and metastatic disease.(a) Kaplan–Meier cumulative survival analysis of Ptenpc−/−IL-6−/− compared with Ptenpc−/− mice; WT and IL-6−/− mice served as controls (P<0.0001; log-rank test). (b) Gross anatomy of representative prostates isolated at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 10 mm. (c) Prostate weights of 38-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Mean values are shown; error bars: s.d. (n=43). (d) Histopathological analysis of haematoxilin/eosin-stained primary PCa and liver at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Arrowhead in the inset: area of nerve sheet infiltration. Scale bars, 100 μm. (e) IHC analysis of Ki-67 and CC3 in prostates from 19-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 100 μm. (f,g) Bar graphs indicate percentage of cells positive for Ki-67 and CC3 (e). Protein levels quantification was done with HistoQuest software (n=5). Data from c, f and g were analysed by Student's t-test and are shown as mean±s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4525303&req=5

f5: Deletion of IL-6 and Pten triggers progressive prostate tumorigenesis and metastatic disease.(a) Kaplan–Meier cumulative survival analysis of Ptenpc−/−IL-6−/− compared with Ptenpc−/− mice; WT and IL-6−/− mice served as controls (P<0.0001; log-rank test). (b) Gross anatomy of representative prostates isolated at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 10 mm. (c) Prostate weights of 38-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Mean values are shown; error bars: s.d. (n=43). (d) Histopathological analysis of haematoxilin/eosin-stained primary PCa and liver at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Arrowhead in the inset: area of nerve sheet infiltration. Scale bars, 100 μm. (e) IHC analysis of Ki-67 and CC3 in prostates from 19-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 100 μm. (f,g) Bar graphs indicate percentage of cells positive for Ki-67 and CC3 (e). Protein levels quantification was done with HistoQuest software (n=5). Data from c, f and g were analysed by Student's t-test and are shown as mean±s.d.

Mentions: IL-6 signalling is the major regulator of Stat3 with therapeutic relevance. To address whether Stat3 activation in Ptenpc−/− mice depends on IL-6 signalling, we crossed Ptenpc−/− mice with IL-6−/− mice30. Co-deletion of IL-6 and Pten triggered early lethality (Fig. 5a), progressive high-grade adenocarcinoma formation with increased tumour growth and weight (Fig. 5b,c), resulting in disseminated metastases (Fig. 5d), for example, in the liver (Supplementary Fig. 8a). Loss of IL-6 in Pten heterozygous prostate tissue also resulted in high-grade invasive PCa with metastasis formation at 15 months of age (Supplementary Fig. 8b). Like Ptenpc−/−Stat3pc−/− mice, Ptenpc−/−IL-6−/− mice showed markedly enhanced PCa growth (Supplementary Fig. 8c,d) at 19 weeks of age, increased Ki-67+ but decreased CC3+ expression levels compared with Ptenpc−/− prostates (Fig. 5e–g). IHC analysis revealed absence of pY-Stat3 and Stat3 expression in Ptenpc−/−IL-6−/− tumours (Supplementary Fig. 8e).


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)

Deletion of IL-6 and Pten triggers progressive prostate tumorigenesis and metastatic disease.(a) Kaplan–Meier cumulative survival analysis of Ptenpc−/−IL-6−/− compared with Ptenpc−/− mice; WT and IL-6−/− mice served as controls (P<0.0001; log-rank test). (b) Gross anatomy of representative prostates isolated at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 10 mm. (c) Prostate weights of 38-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Mean values are shown; error bars: s.d. (n=43). (d) Histopathological analysis of haematoxilin/eosin-stained primary PCa and liver at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Arrowhead in the inset: area of nerve sheet infiltration. Scale bars, 100 μm. (e) IHC analysis of Ki-67 and CC3 in prostates from 19-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 100 μm. (f,g) Bar graphs indicate percentage of cells positive for Ki-67 and CC3 (e). Protein levels quantification was done with HistoQuest software (n=5). Data from c, f and g were analysed by Student's t-test and are shown as mean±s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525303&req=5

f5: Deletion of IL-6 and Pten triggers progressive prostate tumorigenesis and metastatic disease.(a) Kaplan–Meier cumulative survival analysis of Ptenpc−/−IL-6−/− compared with Ptenpc−/− mice; WT and IL-6−/− mice served as controls (P<0.0001; log-rank test). (b) Gross anatomy of representative prostates isolated at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 10 mm. (c) Prostate weights of 38-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Mean values are shown; error bars: s.d. (n=43). (d) Histopathological analysis of haematoxilin/eosin-stained primary PCa and liver at 38 weeks of age from WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Arrowhead in the inset: area of nerve sheet infiltration. Scale bars, 100 μm. (e) IHC analysis of Ki-67 and CC3 in prostates from 19-week-old WT, IL-6−/−, Ptenpc−/− and Ptenpc−/−IL-6−/− mice. Scale bars, 100 μm. (f,g) Bar graphs indicate percentage of cells positive for Ki-67 and CC3 (e). Protein levels quantification was done with HistoQuest software (n=5). Data from c, f and g were analysed by Student's t-test and are shown as mean±s.d.
Mentions: IL-6 signalling is the major regulator of Stat3 with therapeutic relevance. To address whether Stat3 activation in Ptenpc−/− mice depends on IL-6 signalling, we crossed Ptenpc−/− mice with IL-6−/− mice30. Co-deletion of IL-6 and Pten triggered early lethality (Fig. 5a), progressive high-grade adenocarcinoma formation with increased tumour growth and weight (Fig. 5b,c), resulting in disseminated metastases (Fig. 5d), for example, in the liver (Supplementary Fig. 8a). Loss of IL-6 in Pten heterozygous prostate tissue also resulted in high-grade invasive PCa with metastasis formation at 15 months of age (Supplementary Fig. 8b). Like Ptenpc−/−Stat3pc−/− mice, Ptenpc−/−IL-6−/− mice showed markedly enhanced PCa growth (Supplementary Fig. 8c,d) at 19 weeks of age, increased Ki-67+ but decreased CC3+ expression levels compared with Ptenpc−/− prostates (Fig. 5e–g). IHC analysis revealed absence of pY-Stat3 and Stat3 expression in Ptenpc−/−IL-6−/− tumours (Supplementary Fig. 8e).

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