Cytokine-dependent regulation of prostate cancer stem cells maintenance in response to radiotherapy

Purpose: According to the cancer stem cell hypothesis prostate cancer is driven by a malignant subpopulation with stem-like properties. These cancer stem cells (CSC) contribute to tumor-initiation, metastasis, therapy-resistance and tumor relapse. In parallel, genetic mutations accumulate over time and CSC subclones evolve. Therapeutic interventions like radiotherapy provide selective pressure for the expansion of resistant subclones with genetic diversification. We hypothesize that the determination of CSC-related biomarker in prostate cancer biopsies is correlating with clinical parameter and can be used for patient stratification and treatment selection to improve personalized radiotherapy.
Methodology: We generated isogenic radioresistant prostate cancer cell lines with a high expression of CSC marker, a epithelial-to-mesenchymal transition (EMT) phenotype, higher self-renewal properties, higher tumorigenicity and enhanced DNA repair capacity. We applied comparative genomic, proteomic, metabolomic, epigenomic and secretome analysis to identify novel biomarker for prostate cancer radioresistance and to unravel contributing molecular mechanisms.
Results: Within our first proof-of-principle study, we could show that ALDH-positive CSCs are radioresistant and maintained directly by the Wnt/β-catenin signaling pathway (1). In addition, we found that irradiation is inducing CSC marker and CSC properties in a dose- and time-dependent manner. This irradiation-induced CSC-plasticity was attributed to the modulation of the histone methylation code (2). Within the present study we analyzed a panel of secreted cytokines and their corresponding cytokine receptors in the radioresistant prostate cancer sublines, in a s.c. xenotransplantation model, in ex vivo irradiated primary prostate cancer biopsies and in blood samples of prostate cancer patients during the course of radiotherapy and found, for example, the CXCR4-CXCL12 signaling to be involved in the CSC maintenance and the induction of prostate cancer radioresistance.

References:

(1) Peitzsch C, Cojoc M, Hein L, Kurth I, Mäbert K, Trautmann F, Klink B, Schrock E, Wirth MP, Krause M et al: An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells. Cancer research 2016, 76; 2637.

(2) Cojoc M*, Peitzsch C*, Kurth I, Trautmann F, Kunz-Schughart LA, Telegeev GD, Stakhovsky EA, Walker JR, Simin K, Lyle S et al: Aldehyde Dehydrogenase Is Regulated by beta-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer research 2015, 75(7):1482-1494.