Abstract
Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.
| Original language | English |
|---|---|
| Pages (from-to) | 866-876 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 15 Feb 2016 |
Cite this
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IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. / Brooks, Gavin D.; McLeod, Louise; Alhayyani, Sultan; Miller, Alistair; Russell, Prudence A; Ferlin, Walter; Rose-John, Stefan; Ruwanpura, Saleela; Jenkins, Brendan J.
In: Cancer Research, Vol. 76, No. 4, 15.02.2016, p. 866-876.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - IL6 trans-signaling promotes KRAS-driven lung carcinogenesis
AU - Brooks, Gavin D.
AU - McLeod, Louise
AU - Alhayyani, Sultan
AU - Miller, Alistair
AU - Russell, Prudence A
AU - Ferlin, Walter
AU - Rose-John, Stefan
AU - Ruwanpura, Saleela
AU - Jenkins, Brendan J.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.
AB - Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130F/F: KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.
UR - http://www.scopus.com/inward/record.url?scp=84960338835&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2388
DO - 10.1158/0008-5472.CAN-15-2388
M3 - Article
VL - 76
SP - 866
EP - 876
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 4
ER -