Analysis of Several Pathways for Efficient Killing of Prostate Cancer Stem Cells: A Central Role of NF-κB RELA.

Kaya E Witte,Clara Wimmer,Barbara Kaltschmidt,Melanie Lütkemeyer,Jesco Pfitzenmaier,Ludwig Wilkens,Jonathan Storm,Jan Schulte Am Esch,Marvin Geisler,Christian Kaltschmidt,Wiebke Schulten,Fritz Mertzlufft,Christine Förster,Cornelius Knabbe,Nele Czaniera

doi:10.3390/ijms22168901

Abstract

Prostate cancer is a common cause of death worldwide. Here, we isolated cancer stem cells (CSCs) from four adenocarcinomas of the prostate (Gleason scores from 3 + 3 up to 4 + 5). CSCs were characterized by the expression of the stem cell markers TWIST, the epithelial cell adhesion molecule (EPCAM), the transcription factors SNAI1 (SNAIL) and SNAI2 (SLUG) and cancer markers such as CD44 and prominin-1 (CD133). All investigated CSC populations contained a fraction highly positive for aldehyde dehydrogenase (ALDH) function and displayed robust expressions of programmed cell death 1 (PD-1) ligands. Furthermore, we investigated immunotherapeutic approaches but had no success even with the clinically used PD-1 inhibitor pembrolizumab. In addition, we studied another death-inducing pathway via interferon gamma signaling and detected high-level upregulations of human leukocyte antigen A (HLA-A) and beta 2-microglobulin (B2M) with only moderate killing efficacy. To examine further killing mechanisms in prostate cancer stem cells (PCSCs), we analyzed NF-κB signaling. Surprisingly, two patient-specific populations of PCSCs were found: one with canonical NF-κB signaling and another one with blunted NF-κB activation, which can be efficiently killed by tumor necrosis factor (TNF). Thus, culturing of PCSCs and analysis of respective NF-κB induction potency after surgery might be a powerful tool for optimizing patient-specific treatment options, such as the use of TNF-inducing chemotherapeutics and/or NF-κB inhibitors.

Highlights

Prostate cancer (PCa) is the fourth most common cancer worldwide and the most frequent non-cutaneous cancer in men, leading to an estimated 375,000 deaths per year [1].Due to a lack of pathological symptoms before diagnosis [2], in most cases, PCa remains incurable after forming metastases [3]
CD133 is commonly related to stemness properties, it might lead to tumorigenesis, metastasis and chemoresistance in cancer stem cells (CSCs)
epithelial cell adhesion molecule (EPCAM) was expressed in each population, and in a PCa model system, this is associated with epithelial-to-mesenchymal transition (EMT), and might contribute to metastatic plasticity [25]

Summary

Introduction

Prostate cancer (PCa) is the fourth most common cancer worldwide and the most frequent non-cutaneous cancer in men, leading to an estimated 375,000 deaths per year [1].Due to a lack of pathological symptoms before diagnosis [2], in most cases, PCa remains incurable after forming metastases [3]. Prostate cancer (PCa) is the fourth most common cancer worldwide and the most frequent non-cutaneous cancer in men, leading to an estimated 375,000 deaths per year [1]. Most PCa patients exhibit increased plasmatic amounts of prostate-specific antigen (PSA). The screening of PSA in clinical practice, may result in over-diagnosis to some extent [4,5]. In low-risk PCa patients, an active surveillance strategy has turned out to be the most popular option, avoiding therapy that results in side effects and overtreatment [6]. In intermediate and high-risk PCa, curative treatment is favorable, with common treatment options being radiation therapy, androgenablation, and radical prostatectomy [7,8]. High-intensity focused ultrasound or cryotherapy may be chosen, these are mainly used in low- or intermediate-risk

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Conclusion