Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors

Abstract

BACKGROUNDDesmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF‐03084014, a potent γ‐secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β‐catenin pathway. Consequently, Notch pathway inhibition by PF‐03084014 might be a promising approach for DT treatment.METHODSThe expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF‐03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF‐03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis.RESULTSThe results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF‐03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF‐03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1‐inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF‐03084014 through integrin.CONCLUSIONOur findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF‐03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment. Cancer 2015;121:4088–4096. © 2015 American Cancer Society.

Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma

“…Exposure of resistant OS cells to 6 µM CDDP resulted in cell cycle arrest at the G0/G1‐phase in agreement with other scholars studies . We also found that DAPT promoted G0/G1‐phase arrest via reduction of Cyclin D1, Cyclin E1, CDK2, SKP2, c‐Myc and increase p21, which were consistent with the findings of other earlier studies showed that DAPT induces G0/G1‐phase arrest in human OS cells and other tumors . It is not surprising that the G0/G1‐phase arrest induced by CDDP and DAPT combination treatment was significantly greater than monotherapy group.…”

Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway

“…Although Wnt signaling mainly plays a role in the maintenance of adult stem cells, recent studies have explored the integral role of Wnt signaling in cancer stem-like cells [19, 20]. However, in specific environments, Notch, which was identified to be mutually regulated by Wnt, participates in the stemness and differentiation [34]. For example, Notch signaling is likely to inhibit specific differentiation lineages and to maintain the sustainability of self-renewal tumor populations in intestinal epithelial cells, hematopoietic stem cells and esophageal adenocarcinoma cells, and these features are characteristics of stemness [35–37].…”

Results of surgical treatment in patients with abdominal desmoid fibromas

“…Так, в своей работе H. Shang и со-авт. [39] сообщают об обнаружении нового сигнального пути, обусловливающего неконтролируемую пролифера-цию фибробластов -сигнальный путь NOTCH, который представляется потенциально важным и обнадеживаю-щим в плане поиска новых терапевтических агентов. Ле-чебный эффект может быть основан на ингибировании гамма-секретазы, которая в свою очередь блокирует сиг-нальный путь NOTCH, оказывая противоопухолевое воз-действие.…”