Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Abstract

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. We demonstrate that the Hh signaling pathway is activated in lung stroma in a paracrine manner. Genetic deletion of Shh in autochthonous 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 by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, not 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 reactive oxygen species (ROS). Treatment of KP mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor ROS levels, inhibited tumor growth and prolonged mouse survival suggesting that increased ROS levels from stromal Hh pathway inhibition spurred lung tumor growth. Thus, IHH induces stromal Hh pathway activation to suppress tumor growth and metastases, in part, by limiting ROS production.

Keratin19 promotes pancreatic cancer progression and poor prognosis via activating the Hedgehog pathway

“…When the ligands [Sonic hedgehog (Shh), Ihh and desert hedgehog] are combined with PTCH (PTCH1 and PTCH2), SMO increases and releases Gli1, Gli2 and Gli3 transcription factors, which promote transcription of Gli1, Gli2 and Gli3. As a result, the Hedgehog pathway is activated (15,22,35). Therefore, to investigate the mechanism by which K19 affects the progression and prognosis of pancreatic cancer, the expression of Ihh, PTCH, SMO and Gli1 in pancreatic cancer was observed.…”

Targeting cancer stem cell pathways for lung cancer therapy

“…The Hedgehog (HH) signaling pathway has been given evidence of essential roles in maintaining hematopoietic stem cells, and its aberrant activities have also been linked to various solid tumors [48,49]. Briefly, paracrine mechanisms of mammalian HH ligands and combination with Patched (PTCH) could partially relieve the effects of disinhibition on Smoothened (SMO) to initiate the transcription of target genes (Fig.…”