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Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer

Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been i...

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Autores principales: Wang, Da, Nagle, Peter W., Wang, Helena H., Smit, Justin K., Faber, Hette, Baanstra, Mirjam, Karrenbeld, Arend, Chiu, Roland K., Plukker, John Th.M., Coppes, Robert P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627376/
https://www.ncbi.nlm.nih.gov/pubmed/31200527
http://dx.doi.org/10.3390/cancers11060821
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author Wang, Da
Nagle, Peter W.
Wang, Helena H.
Smit, Justin K.
Faber, Hette
Baanstra, Mirjam
Karrenbeld, Arend
Chiu, Roland K.
Plukker, John Th.M.
Coppes, Robert P.
author_facet Wang, Da
Nagle, Peter W.
Wang, Helena H.
Smit, Justin K.
Faber, Hette
Baanstra, Mirjam
Karrenbeld, Arend
Chiu, Roland K.
Plukker, John Th.M.
Coppes, Robert P.
author_sort Wang, Da
collection PubMed
description Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy resistance, as well as in cancer stemness. This article focusses on the HH pathway as a putative target in the treatment of EC. Immunohistochemistry on HH members was applied to EC patient material followed by modulation of 3D-EC cell cultures, fluorescence-activated cell sorting (FACS), and gene expression analysis after HH pathway modulation. Sonic Hedgehog (SHH) and its receptor Patched1 (PTCH1) were significantly enriched in EC resection material of patients with microresidual disease (mRD) after receiving nCRT, compared to the control group. Stimulation with SHH resulted in an up-regulation of cancer stemness in EC sphere cultures, as indicated by increased sphere formation after sorting for CD44+/CD24− EC cancer stem-like cell (CSC) population. On the contrary, inhibiting this pathway with vismodegib led to a decrease in cancer stemness and both radiation and carboplatin resistance. Our results strengthen the role of the HH pathway in chemoradiotherapy resistance. These findings suggest that targeting the HH pathway could be an attractive approach to control CSCs.
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spelling pubmed-66273762019-07-23 Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer Wang, Da Nagle, Peter W. Wang, Helena H. Smit, Justin K. Faber, Hette Baanstra, Mirjam Karrenbeld, Arend Chiu, Roland K. Plukker, John Th.M. Coppes, Robert P. Cancers (Basel) Article Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy resistance, as well as in cancer stemness. This article focusses on the HH pathway as a putative target in the treatment of EC. Immunohistochemistry on HH members was applied to EC patient material followed by modulation of 3D-EC cell cultures, fluorescence-activated cell sorting (FACS), and gene expression analysis after HH pathway modulation. Sonic Hedgehog (SHH) and its receptor Patched1 (PTCH1) were significantly enriched in EC resection material of patients with microresidual disease (mRD) after receiving nCRT, compared to the control group. Stimulation with SHH resulted in an up-regulation of cancer stemness in EC sphere cultures, as indicated by increased sphere formation after sorting for CD44+/CD24− EC cancer stem-like cell (CSC) population. On the contrary, inhibiting this pathway with vismodegib led to a decrease in cancer stemness and both radiation and carboplatin resistance. Our results strengthen the role of the HH pathway in chemoradiotherapy resistance. These findings suggest that targeting the HH pathway could be an attractive approach to control CSCs. MDPI 2019-06-13 /pmc/articles/PMC6627376/ /pubmed/31200527 http://dx.doi.org/10.3390/cancers11060821 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Da
Nagle, Peter W.
Wang, Helena H.
Smit, Justin K.
Faber, Hette
Baanstra, Mirjam
Karrenbeld, Arend
Chiu, Roland K.
Plukker, John Th.M.
Coppes, Robert P.
Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title_full Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title_fullStr Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title_full_unstemmed Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title_short Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer
title_sort hedgehog pathway as a potential intervention target in esophageal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627376/
https://www.ncbi.nlm.nih.gov/pubmed/31200527
http://dx.doi.org/10.3390/cancers11060821
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