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Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance

Kai-Jian Wang1, Chao Wang1, Li-He Dai1

  • 1Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 7, 2018
PubMed
Abstract

Insights

Blocking a specific signaling loop in cancer stem cells can overcome chemotherapy resistance in bladder cancer. This finding offers a potential new treatment strategy for advanced bladder cancer patients.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Chemotherapy Resistance Mechanisms

Background:

  • Cancer stem-like cells (CSCs) are implicated in bladder cancer progression and resistance to chemotherapy.
  • The precise molecular mechanisms driving CSC-mediated resistance remain incompletely understood.
  • This study investigates a potential autocrine signaling loop within CSCs contributing to therapeutic failure.

Purpose of the Study:

  • To determine if inhibiting an autocrine signaling loop in bladder cancer stem cells can enhance the efficacy of cisplatin chemotherapy.
  • To elucidate the role of OV6 expression and associated signaling pathways in bladder cancer stem cell properties and chemoresistance.

Main Methods:

  • Immunohistochemistry (IHC) was used to assess OV6 expression in human bladder cancer tissues.
  • Magnetic-activated cell sorting (MACS) isolated OV6+ and OV6- bladder cancer cells for functional assays.
  • Molecular analyses included RNA-Seq, cytokine arrays, co-IP, ChIP, and an orthotopic mouse model to test YAP and PDGFR inhibitors.

Main Results:

  • High OV6 expression correlated with advanced bladder cancer, poor prognosis, and enhanced CSC characteristics (self-renewal, tumor initiation, chemoresistance).
  • The YAP/TEAD1 pathway was identified as crucial for maintaining OV6+ CSC stemness and triggering PDGFB transcription.
  • Inhibition of the YAP/TEAD1/PDGF-BB/PDGFR signaling loop using verteporfin or CP-673451 significantly reduced cisplatin resistance in OV6+ bladder cancer CSCs in vivo.

Conclusions:

  • OV6 serves as a potential biomarker for bladder cancer progression and patient prognosis.
  • Targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR signaling loop represents a promising therapeutic strategy to overcome cisplatin resistance.
  • This approach may offer a novel treatment option for patients with advanced bladder cancer exhibiting chemoresistance.

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