Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma

Abstract

BackgroundThe Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors.MethodsPDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling.ResultsPrecision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model.ConclusionHh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

Exosomal Sonic Hedgehog derived from cancer‐associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma

“…Some scholars demonstrated that the expression of SHH are associated with the survival outcome of the neoadjuvant chemoradiotherapy (nCRT) in patients with ESCC, and the expression of PTCH1 and Gli1 may be significantly associated with ESCC resistance to chemoradiotherapy . Furthermore, inhibition of Hedgehog signaling can regulate radiation sensitivity in mouse xenograft models of human esophageal cancer . So, targeting the SHH pathway may become a novel approach to prevent or inhibit the progression of ESCC, this is consistent with our point of view.…”

“…51 Furthermore, inhibition of Hedgehog signaling can regulate radiation sensitivity in mouse xenograft models of human esophageal cancer. 52 So, targeting the SHH pathway may become a novel approach to prevent or inhibit the progression of ESCC, this is consistent with our point of view. In our study, we found that inhibiting the exosomal transfer of SHH from CAFs to cancer cells can influence the progression of ESCC in vivo and in vitro.…”

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

“…In vivo inhibition of Shh pathway by Gli antagonist (GANT61), a Smo-inhibitor, has synergistic effect with radiotherapy in xenograft model of prostate cancer [ 144 ]. A monoclonal anti-Shh antibody, 5E1 or LED225 (Novartis) was able to increase the efficacy of radiation treatment in patient-derived xenograft models of cervical and esophageal cancer [ 145 , 146 ]. Clinically, expression of Shh pathway (Gli1 staining) was associated with the efficacy of esophageal patients treated with chemoradiation and surgery, in two cohorts of patients ( n = 60 and n = 167) [ 147 ].…”

Hedgehog signaling enables repair of ribosomal DNA double-strand breaks

“…Treatment of TNBC relies on DNA-damaging agents, including conventional chemotherapy and IR ( 30 ). Though inhibiting Hh has been shown to sensitize cancer cells to genotoxic therapies, the underlying mechanisms to this point have remained vague ( 12 , 13 ). Our study has uncovered an unexpected role for Hh signaling in the repair of damaged rDNA that helps to explain this phenomenon.…”

“…We showed that GLI1 upregulates expression of NER and BER genes in response to SSBs to facilitate their repair ( 11 ). Hh inhibition is also known to sensitize cancer cells to agents that induce DSBs, but the mechanisms by which Hh influences DSB repair are poorly understood ( 12 , 13 ). We hypothesized that induction of DSBs by ionizing radiation (IR) would result in cistromic changes in GLI1 in order to orchestrate the activation of DNA repair programs.…”