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Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)

TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival i...

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Autores principales: Alam, Md Maksudul, Fermin, Janmaris Marin, Knackstedt, Mark, Noonan, Mackenzie J., Powell, Taylor, Goodreau, Landon, Daniel, Emily K., Rong, Xiaohua, Moore-Medlin, Tara, Khandelwal, Alok R., Nathan, Cherie-Ann O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901561/
https://www.ncbi.nlm.nih.gov/pubmed/36745547
http://dx.doi.org/10.18632/oncotarget.28355
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author Alam, Md Maksudul
Fermin, Janmaris Marin
Knackstedt, Mark
Noonan, Mackenzie J.
Powell, Taylor
Goodreau, Landon
Daniel, Emily K.
Rong, Xiaohua
Moore-Medlin, Tara
Khandelwal, Alok R.
Nathan, Cherie-Ann O.
author_facet Alam, Md Maksudul
Fermin, Janmaris Marin
Knackstedt, Mark
Noonan, Mackenzie J.
Powell, Taylor
Goodreau, Landon
Daniel, Emily K.
Rong, Xiaohua
Moore-Medlin, Tara
Khandelwal, Alok R.
Nathan, Cherie-Ann O.
author_sort Alam, Md Maksudul
collection PubMed
description TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.
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spelling pubmed-99015612023-02-07 Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC) Alam, Md Maksudul Fermin, Janmaris Marin Knackstedt, Mark Noonan, Mackenzie J. Powell, Taylor Goodreau, Landon Daniel, Emily K. Rong, Xiaohua Moore-Medlin, Tara Khandelwal, Alok R. Nathan, Cherie-Ann O. Oncotarget Research Paper TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling. Impact Journals LLC 2023-02-02 /pmc/articles/PMC9901561/ /pubmed/36745547 http://dx.doi.org/10.18632/oncotarget.28355 Text en Copyright: © 2023 Alam et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Alam, Md Maksudul
Fermin, Janmaris Marin
Knackstedt, Mark
Noonan, Mackenzie J.
Powell, Taylor
Goodreau, Landon
Daniel, Emily K.
Rong, Xiaohua
Moore-Medlin, Tara
Khandelwal, Alok R.
Nathan, Cherie-Ann O.
Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title_full Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title_fullStr Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title_full_unstemmed Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title_short Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)
title_sort everolimus downregulates stat3/hif-1α/vegf pathway to inhibit angiogenesis and lymphangiogenesis in tp53 mutant head and neck squamous cell carcinoma (hnscc)
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901561/
https://www.ncbi.nlm.nih.gov/pubmed/36745547
http://dx.doi.org/10.18632/oncotarget.28355
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