Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece.
Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece.
Cells. 2022 Aug 7;11(15):2449. doi: 10.3390/cells11152449.
Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related 'hubs' such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR-Hippo-Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.
前列腺癌属于激素依赖性癌症，是全球男性癌症发病率的主要原因。由于疾病发生时几乎所有的前列腺癌都依赖雄激素，并且需要活跃的雄激素受体 (AR) 信号来维持其生存，因此主要的治疗方法几十年来一直依赖于通过雄激素剥夺疗法 (ADT) 抑制 AR 通路。然而，采用这种治疗方法后，癌细胞池往往会对治疗产生耐药性，导致疾病向侵袭性更强的去势抵抗性前列腺癌 (CRPC) 发展，预后较差。因此，阐明早期前列腺癌向 CRPC 发展的分子机制和信号通路至关重要。在这篇综述中，我们旨在阐明包括 DNA 损伤反应 (DDR) 和发育中的 Hippo 和 Notch 通路在内的主要信号通路在前列腺肿瘤发生中的作用。我们总结了关键证据，证明了这些通路之间以及与 AR 信号等关键的前列腺癌相关“枢纽”之间的相互作用，并评估了这些相互作用的临床影响。此外，我们试图确定复杂的 DDR-Hippo Notch 相互作用中的分子，这些分子可能是对抗前列腺肿瘤发生的潜在新的治疗靶点。
