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A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in

Haiyan Zhu1,2, Xiang Gu2, Lu Xia2,3

  • 1Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 18, 2018
PubMed

Insights

Chemotherapy activates the TGFβ pathway, promoting cancer stem cell traits and reducing treatment effectiveness. A novel TGFβ trap, RER, blocks this activation and enhances antitumor activity in gynecologic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chemotherapy can inadvertently activate the transforming growth factor beta (TGFβ) pathway.
  • This activation is linked to the development of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics.
  • These changes can lead to reduced sensitivity to chemotherapy and poorer treatment outcomes in gynecologic cancers.

Purpose of the Study:

  • To elucidate the mechanisms by which chemotherapeutics activate the TGFβ pathway.
  • To evaluate the efficacy of a novel TGFβ trap, RER, in blocking chemotherapy-induced TGFβ activation.
  • To assess the potential of RER in combination therapy to enhance antitumor activity in gynecologic cancers.

Main Methods:

  • Bioinformatic analysis of gene expression in chemotherapy-treated ovarian cancer.
  • Immunohistochemical detection of phosphorylated Smad2 in cervical cancer tissues.
  • In vitro and in vivo studies using gynecologic cancer cells and xenograft models to assess TGFβ signaling, EMT, CSC markers, and tumor growth inhibition.

Main Results:

  • Chemotherapy-induced transcriptome alterations in ovarian cancer were significantly associated with TGFβ pathway activation.
  • Chemotherapy treatment increased phosphorylated Smad2 levels in cervical cancer, indicating TGFβ pathway activation.
  • Chemotherapeutics stimulated TGFβ1 production, leading to increased Smad2/3 phosphorylation, cell migration, EMT, and CSC markers, which were abrogated by RER.
  • Combination therapy with RER and cisplatin demonstrated superior tumor inhibitory activity compared to monotherapy in an ovarian cancer xenograft model.

Conclusions:

  • Chemotherapeutics stimulate TGFβ1 production, enhancing TGFβ signaling, EMT, and CSC features, which contributes to chemoresistance.
  • A novel TGFβ trap, RER, effectively inhibits chemotherapy-induced TGFβ signaling and its downstream effects.
  • Combination therapy involving RER and chemotherapy holds promise for overcoming chemoresistance and improving therapeutic efficacy in gynecologic cancers.

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