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Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)

  • Authors:
    • Yun-Fan Li
    • Shuai Su
    • Yu Luo
    • Chengcheng Wei
    • Jingke He
    • Liang-Dong Song
    • Kun Han
    • Jue Wang
    • Xiangzhi Gan
    • De-Lin Wang
  • View Affiliations / Copyright

    Affiliations: Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 109
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    Published online on: July 4, 2025
       https://doi.org/10.3892/or.2025.8942
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Abstract

Neuroendocrine (NE) prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer. It is typically characterized by the expression of NE markers and the loss of androgen receptor expression. De novo NEPC is rare, accounting for <2% of all prostate cancer cases at diagnosis. More commonly, NEPC arises from prostate adenocarcinoma following androgen deprivation therapy, with 20‑25% of metastatic castration‑resistant prostate cancers undergoing NE differentiation due to lineage plasticity. During this transition, pathways associated with epithelial‑mesenchymal transition (EMT) and stemness are broadly activated, which is considered to be a key driver of NEPC's high metastatic potential, resistance to chemotherapy and radiotherapy and poor prognosis. EMT facilitates metastasis by enhancing cellular motility and invasiveness, while stemness properties contribute to post‑metastatic colonization, immune evasion, therapy resistance and cellular dormancy. As manifestations of cellular plasticity, these processes share overlapping molecular mechanisms. Targeting key regulators within these pathways may offer promising therapeutic strategies for NEPC.
View Figures

Figure 1

The development of NEPC which
influenced by ADT, EMT and stemness. Normal prostate luminal
epithelial cells and basal epithelial cells can undergo malignant
transformation into normal tumor cells. After ADT, 10–20% of
prostate adenocarcinomas transform into CRPC. With further ADT
treatment, 20–25% of CRPC can transition into NEPC. During this
process, while AR (androgen receptor) signaling is inhibited, the
EMT process is activated and plays a critical role in castration
resistance, metastasis and NED. Cancer cells often undergo
dedifferentiation under the therapeutic pressure of ADT,
chemotherapy and radiation oncology. CSCs may originate from
malignant mutations of normal stem cells, with the TME playing a
significant role in this process. Normal tumor cells can become
CTCs through EMT and a small subset of CTCs survive by activating
stemness, thereby acquiring immune evasion and dormancy, which
gives them an opportunity to colonize. These surviving stem-like
tumor cells, due to their multilineage differentiation potential,
may be an important source of NEPC. NEPC, neuroendocrine prostate
cancer; ADT, androgen deprivation therapy; EMT,
epithelial-mesenchymal transition; CRPC, castration-resistant
prostate cancer; NED neuroendocrine differentiation; TME, tumor
microenvironment; CTCs, circulating tumor cells

Figure 2

The simplified association among ADT,
EMT, stemness and NED in prostate cancer. ADT concurrently promotes
EMT, stemness and NED; EMT facilitates stemness and NED; and
stemness drives NED. ADT, androgen deprivation therapy; EMT,
epithelial-mesenchymal transition; NED neuroendocrine
differentiation.
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Copy and paste a formatted citation
Spandidos Publications style
Li Y, Su S, Luo Y, Wei C, He J, Song L, Han K, Wang J, Gan X, Wang D, Wang D, et al: Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review). Oncol Rep 54: 109, 2025.
APA
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L. ... Wang, D. (2025). Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review). Oncology Reports, 54, 109. https://doi.org/10.3892/or.2025.8942
MLA
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L., Han, K., Wang, J., Gan, X., Wang, D."Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)". Oncology Reports 54.3 (2025): 109.
Chicago
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L., Han, K., Wang, J., Gan, X., Wang, D."Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)". Oncology Reports 54, no. 3 (2025): 109. https://doi.org/10.3892/or.2025.8942
Copy and paste a formatted citation
x
Spandidos Publications style
Li Y, Su S, Luo Y, Wei C, He J, Song L, Han K, Wang J, Gan X, Wang D, Wang D, et al: Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review). Oncol Rep 54: 109, 2025.
APA
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L. ... Wang, D. (2025). Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review). Oncology Reports, 54, 109. https://doi.org/10.3892/or.2025.8942
MLA
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L., Han, K., Wang, J., Gan, X., Wang, D."Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)". Oncology Reports 54.3 (2025): 109.
Chicago
Li, Y., Su, S., Luo, Y., Wei, C., He, J., Song, L., Han, K., Wang, J., Gan, X., Wang, D."Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)". Oncology Reports 54, no. 3 (2025): 109. https://doi.org/10.3892/or.2025.8942
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