IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.

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 gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) 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 trans-signaling, 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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Brooks GD,McLeod L,Alhayyani S,Miller A,Russell PA,Ferlin W,Rose-John S,Ruwanpura S,Jenkins BJ

doi

10.1158/0008-5472.CAN-15-2388

subject

Has Abstract

pub_date

2016-02-15 00:00:00

pages

866-76

issue

4

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-15-2388

journal_volume

76

pub_type

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