Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species
| Autor: | Luc Girard, Sahba Kasiri, Ummay Marriam, Barbara Mino, Jashkaran Gadhvi, Katherine Luby-Phelps, Annika Reczek, Baozhi Chen, Evan Noel, Wei Lu, Simbarashe Mazambani, Justin A. Bishop, Luisa M. Solis, Alexandra N. Wilson, Jung Whan Kim, James Kim |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer microenvironment
0301 basic medicine Cancer Research Stromal cell DNA damage Adenocarcinoma of Lung Biology Ligands Article Metastasis Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Stroma Genetics medicine Animals Humans Hedgehog Proteins Neoplasm Metastasis Cancer models Lung Molecular Biology Hedgehog Cell Proliferation 030304 developmental biology 0303 health sciences Chemistry medicine.disease Hedgehog signaling pathway Acetylcysteine Antibodies Anti-Idiotypic Gene Expression Regulation Neoplastic Mechanisms of disease 030104 developmental biology 030220 oncology & carcinogenesis Mutation Cancer research Blood Vessels Adenocarcinoma Tumor Suppressor Protein p53 Signal transduction Reactive Oxygen Species Non-small-cell lung cancer Tumour angiogenesis DNA Damage Signal Transduction |
| Zdroj: | Oncogene |
| DOI: | 10.1101/747915 |
| Popis: | Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. Here, we demonstrate that the canonical Hh signaling pathway is activated in lung stroma by Hh ligands secreted from transformed lung epithelia. Genetic deletion ofShh, the primary Hh ligand expressed in the lung, inKrasG12D/+;Trp53fl/flautochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH, another Hh ligand, by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, rather than SHH, activates the pathway in stroma to drive its tumor suppressive effects—a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased DNA damage suggestive of reactive oxygen species (ROS) activity. Treatment ofKrasG12D/+;Trp53fl/flmice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor DNA damage, inhibited tumor growth and prolonged mouse survival. Thus, IHH induces stromal activation of the canonical Hh signaling pathway to suppress tumor growth and metastases, in part, by limiting ROS activity. |
| Databáze: | OpenAIRE |
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