Dr. Weeks’ Comment: As with any and all cancer, the cancer STEM cell is the most critical target.
Targeting Prostate Cancer STEM Cells
The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis
Wenjuan Mei 1 2 3 4 5, Xiaozeng Lin 6 7 8 9, Anil Kapoor 10 11 12, Yan Gu 13 14 15 16, Kuncheng Zhao 17 18 19 20, Damu Tang 21 22 23 24
Cancers (Basel). 2022 Nov 5;14(21):5448.
Abstract
Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial⁻mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types.
AND
Prostate cancer stem cells: from theory to practice
Jan Adamowicz 1, Katayoon Pakravan 2, Babak Bakhshinejad 2, Tomasz Drewa 1, Sadegh Babashah 2
Scand J Urol. 2017 Apr;51(2):95-106.
doi: 10.1080/21681805.2017.1283360. Epub 2017 Feb 7.
DOI: 10.1080/21681805.2017.1283360
Abstract
None of the generally accepted theories on prostate cancer development can fully explain many distinguishing features of the disease, such as intratumoral heterogeneity, metastatic growth, drug resistance and tumor relapse. Prostate stem cells are a heterogeneous and small subpopulation of self-renewing cells which can actively proliferate in response to changes in the androgen level and give rise to all the cell lineages that build the prostate epithelium. According to the cancer stem cell hypothesis, prostate cancer could be a stem cell disease. Prostate cancer stem cells, which represent only a minimal percentage of the tumor mass, are characterized by a markedly increased clonogenicity and therapeutic resistance. These tumor-initiating cells reside in dynamic niches distributed within the prostate but at a higher concentration in proximal regions of the prostatic ducts. Several markers have been used to identify prostate cancer stem cells. Nevertheless, a definitive profile has not yet been established owing to specificity issues. As cancer stem cells play determining roles in the birth and burst of prostate malignancy, strategies that selectively target them have gained huge clinical attention. Unraveling the mechanisms underlying the physiological functions of cancer stem cells and gaining fundamental insights into their putative involvement in the pathogenesis of prostate tumors provide novel opportunities for the development of efficient and sophisticated therapeutic strategies in the future.
AND
Stem Cells as Target for Prostate cancer Therapy: Opportunities and Challenges
Claudia Escudero-Lourdes 1, Ildemar Alvarado-Morales 2, Erik J Tokar 3
- Stem Cell Rev Rep. 2022 Dec;18(8):2833-2851.
- doi: 10.1007/s12015-022-10437-6. Epub 2022 Aug 11.
Abstract
Cancer stem cells (CSCs) and cells in a cancer stem cell-like (CSCL) state have proven to be responsible for tumor initiation, growth, and relapse in Prostate Cancer (PCa) and other cancers; therefore, new strategies are being developed to target such cellular populations. TLR3 activation-based immunotherapy using Polyinosinic:Polycytidylic acid (PIC) has been proposed to be used as a concomitant strategy to first-line treatment. This strategy is based on the induction of apoptosis and an inflammatory response in tumor cells. In combination with retinoids like 9cRA, this treatment can induce CSCs differentiation and apoptosis. A limitation in the use of this combination is the common decreased expression of TLR3 and its main positive regulator p53. observed in many patients suffering of different cancer types such as PCa. Importantly, human exposure to certain toxicants, such as iAs, not only has proven to enrich CSCs population in an in vitro model of human epithelial prostate cells, but additionally, it can also lead to a decreased p53, TLR3 and RA receptor (RARβ), expression/activation and thus hinder this treatment efficacy. Therefore, here we point out the relevance of evaluating the TLR3 and P53 status in PCa patients before starting an immunotherapy based on the use of PIC +9cRA to determine whether they will be responsive to treatment. Additionally, the use of strategies to overcome the lower TLR3, RARβ or p53 expression in PCa patients, like the inclusion of drugs that increase p53 expression, is encouraged, to potentiate the use of PIC+RA based immunotherapy in these patients.
AND
[Prostate cancer stem cells: Current understanding]
[Article in Chinese]
Xing Zhang 1 2, Zi-Yang Han 1, Yun Chen 1
Zhonghua Nan Ke Xue. 2021 Feb;27(2):172-176.
Abstract
Prostate cancer is the most common malignancy in men and seriously harms their health. The current theories on prostate cancer cannot fully explain the heterogeneity, metastatic growth, drug resistance and tumor recurrence of the disease. Prostate stem cells are small heterogeneous subpopulations in the prostate that are characterized by self-renewal and proliferation, and can produce all the lineages of prostate epithelia. According to the cancer stem cell hypothesis, prostate cancer may be a stem cell disease. Prostate cancer stem cells have a markedly increased clonogenicity and therapeutic resistance, and play a decisive role in the occurrence and development of prostatic malignancies. Therapeutic strategies for selectively targeting these stem cells have attracted widespread attention. This article focuses on the origin, identification, molecular markers and clinical application of prostate cancer stem cells, their physiological function and possible involvement in the pathogenesis of prostate cancer, paving a theoretical ground for the development of efficient and sophisticated therapeutic strategies.
AND
Prostate Cancer Stem Cells: The Role of CD133
Jianhui Yang 1, Omar Aljitawi 1, Peter Van Veldhuizen 1
Cancers (Basel). 2022 Nov 5;14(21):5448.
doi: 10.3390/cancers14215448.
Abstract
Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. In this article, we focus on reviewing the role of CD133 in PCSC. Any other main stem cell biomarkers in PCSC reported from key publications, as well as about vital research progress of CD133 in CSCs of different cancers, will be selectively reviewed to help us inform the main topic.