Everolimus Inhibits Angiogenesis, Lymphangiogenesis in TP53 Mutant HNSCC | Oncotarget
Channel: Oncotarget
Date: 09/02/2023

Oncotarget published this trending research paper in Volume 14, entitled, “Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)" by researchers from the Department of Otolaryngology-Head and Neck Surgery, LSU-Health Sciences Center, Shreveport, LA; School of Medicine, LSU-Health Sciences Center, Shreveport, LA; Feist-Weiller Cancer Center, LSU-Health Sciences Center, Shreveport.
#openaccess  #cancer  #research #headandneckcancer   #carcinoma  #openscience  #peerreview  #journal  #publication #oncologyresearch

DOI - https://doi.org/10.18632/oncotarget.28355

Correspondence to - Cherie-Ann O. Nathan - cherieann.nathan@lsuhs.edu 

Abstract

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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Keywords - TP53 mutant, HNSCC, angiogenesis, everolimus, mTOR

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