Stoyanova Tanya, Riedinger Mireille, Lin Shu, Faltermeier Claire M, Smith Bryan A, Zhang Kelvin X, Going Catherine C, Goldstein Andrew S, Lee John K, Drake Justin M, Rice Meghan A, Hsu En-Chi, Nowroozizadeh Behdokht, Castor Brandon, Orellana Sandra Y, Blum Steven M, Cheng Donghui, Pienta Kenneth J, Reiter Robert E, Pitteri Sharon J, Huang Jiaoti, Witte Owen N
Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6457-E6466. doi: 10.1073/pnas.1614529113. Epub 2016 Sep 30.
Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.
转移性去势抵抗性前列腺癌（CRPC）是前列腺癌特异性死亡的主要原因。确定能够预测复发并导致致命性CRPC的新机制至关重要。在此，我们证明局限性高危前列腺癌和转移性CRPC，而非良性前列腺组织或低/中危前列腺癌，表达高水平的核Notch同源物1、易位相关（Notch1）受体胞内结构域。Notch1的慢性激活与早期疾病中改变的多种致癌途径协同作用，以促进前列腺腺癌的发展。这些肿瘤表现出上皮-间质转化的特征，这是一种与肿瘤侵袭性增加相关的细胞状态。与其在临床CRPC中的激活情况一致，由Notch1胞内结构域与前列腺癌中改变的多种途径共同驱动的肿瘤具有转移性且对雄激素剥夺有抗性。我们的研究提供了功能证据，表明Notch1信号轴在促进转移性CRPC方面与其他途径协同作用，可能代表晚期前列腺癌的一个新治疗靶点。
