Prostate Cancer Stem Cells: Biology and Treatment Implications

Abstract

Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas are sustained by the presence of a vital cellular compartment resembling stem cells residing in normal tissues: ‘stem-like cancer cells’ or cancer stem cells (CSCs). Mutations in prostate stem cells can lead to the formation of prostate cancer. Prostate CSCs (PCSCs) have been identified and partially characterized. These express surface markers include CD44, CD133, integrin α2β1, and pluripotency factors like OCT4, NANOG, and SOX2. Several signaling pathways are also over-activated, including Notch, PTEN/Akt/PI3K, RAS-RAF-MEK-ERK and HH. Moreover, PCSCs appear to induce resistance to radiotherapy and chemotherapy, while their presence has been linked to aggressive cancer behavior and higher relapse rates. The development of treatment policies to target PCSCs in tumors is appealing as radiotherapy and chemotherapy, through cancer cell killing, trigger tumor repopulation via activated stem cells. Thus, blocking this reactive stem cell mobilization may facilitate a positive outcome through cytotoxic treatment.

CD44 and its implication in neoplastic diseases

“…CD44 is involved in prostate cancer, and different CD44 isoforms play different roles in tumor progression and stemness. 104 , 105 , 106 A recent study showed that TGF‐β1‐mediated alternative splicing could switch CD44v to CD44s, which enhanced EMT and stemness in human prostate cancer cells. 107 In DU145 and PC3 prostate cancer cells, the high expression of CD44v4, v5, and v7 mediated by sulforaphane contributed to tumor cell growth and proliferative activity.…”

Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression

“…Targeting various signaling pathways, including the Notch, Hedgehog, Wnt, and ABC transporter pathways, as well as the TME, may effectively control PCSCs ( Li et al, 2017 ; Skvortsov et al, 2018 ). Several approaches have been devised to target these pathways, specifically using inhibitors or RNA silencing techniques ( Koukourakis et al, 2023 ; Ramesh et al, 2023 ). Specifically, preclinical and clinical trials have assessed the efficacy of targeting the Notch pathway {RO4929097 [( Stein et al, 2012 ) and PF-03084014 ( Du et al, 2018 ; Wang et al, 2020 )], [Hedgehog pathway (sonidegib ( Nanta et al, 2013 ), Gant-61 ( Rimkus et al, 2016 ), and GDC-0449 ( Tong et al, 2018 )], Wnt pathway (LGK974 ( Liu et al, 2013 ), OMP-54F28 ( Le et al, 2015 ), Foxy-5 ( Kelsey, 2017 ), and OMP-18R5 ( Gurney et al, 2012 )], and [ABC transporter protein pathways (cyclosporin A ( Kawahara et al, 2015 ), dofequidar fumarate ( Katayama et al, 2009 ), and vandetanib ( Horti et al, 2009 ; Azad et al, 2014 )]}.…”

Chronic High-Salt Diet Activates Tumor-Initiating Stem Cells Leading to Breast Cancer Proliferation

“…Studies by Al-Hajj et al provided some of the first proof-of-concept evidence for the existence of a unique subset of CD44+CD24-TISCs in immunocompromised preclinical murine tumor models with human breast cancer cell xenografts [ 17 ]. The presence of these TISCs was later proven in multiple solid organ tumors [ 18 , 19 , 20 , 21 ]. Further, TISCs have been shown to exert immune privilege, due to which, during the elimination phase of tumor immune editing, they are protected from cell death, allowing them to survive until the immune-escape phase, during which they will replicate and differentiate into cancer cells along with recruiting immunosuppressive cells such as MDSCs and FoxP3+ regulatory CD4+T cells (Tregs) [ 22 , 23 , 24 ].…”