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Plasticity within Aldehyde Dehydrogenase-Positive Cells Determines Prostate Cancer Radiosensitivity.

Franziska M Schwarz1,2,3, Iñaki Schniewind2,4, Maria J Besso5

  • 1Institute of Radiooncology - OncoRay, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

Molecular Cancer Research : MCR
|February 9, 2022
PubMed
Summary
This summary is machine-generated.

Irradiation increases stem-like aldehyde dehydrogenase-positive (ALDH+) prostate cancer cells, driving tumor growth and potentially causing radiotherapy failure by promoting radioresistance.

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Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Prostate Cancer Research

Background:

  • Tumor heterogeneity and cellular plasticity, driven by cancer stem cells (CSCs), significantly impact tumor progression, metastasis, and treatment outcomes.
  • The aldehyde dehydrogenase (ALDH) positive (ALDH+) cell population is associated with stem-like properties and therapeutic resistance in various cancers.

Purpose of the Study:

  • To investigate irradiation-induced plasticity within the ALDH+ population in prostate cancer.
  • To analyze the radiosensitivity, transcriptional heterogeneity, and competitive dynamics between ALDH+ and ALDH- cells following irradiation.

Main Methods:

  • Xenograft tumor models derived from ALDH+ and ALDH- prostate cancer cells.
  • Local tumor control analyses to determine radiosensitivity and relapse patterns.
  • Multiplex gene expression analysis for transcriptional heterogeneity.
  • Fluorescence protein-labeled cells for phenotypic conversion and clonal competition studies.
  • Probabilistic Markov compartment modeling.

Main Results:

  • ALDH+ cells exhibit distinct radiosensitivity profiles and outcompete ALDH- cells, driving tumor growth, especially after irradiation.
  • Irradiation increases transcriptional heterogeneity within the ALDH+ population.
  • A Markov model accurately reproduced in vivo cellular dynamics, incorporating plasticity, competition, and radiosensitivity.
  • Cellular conversion from ALDH- to ALDH+ under therapeutic pressure is partly mediated by SNAI2 induction.

Conclusions:

  • Irradiation induces cellular conversion and enhances the stem-like ALDH+ population in prostate cancer xenografts.
  • This irradiation-induced plasticity and increase in ALDH+ cells may represent a mechanism of tumor radioresistance, contributing to radiotherapy failure.