基于磁共振DTI技术的前列腺癌周围神经侵犯(PNI)机制的研究

Prostate cancer death remains continuously and dramatically rising in China, mainly due to lack of a deeper understanding of growth and progression mechanisms of prostate cancer. For these reasons, in-depth studies of growth and progression mechanisms and potential therapeutic targets associated with perineural invasion (PNI) in prostate cancer have important theoretical and clinical value. In the previous studies of imaging in risk assessment of prostate cancer, the applicants have demonstrated diffusion tensor imaging (DTI)-based fiber tracking in prostate cancer. FA values and ADC values were correlated with Gleason scores in the evaluation of tumor aggressiveness, respectively, strongly suggesting the possibility of DTI-based fiber tracking, FA values and ADC values to clarify the underlying growth and progression mechanisms and potential therapeutic targets associated with PNI in prostate cancer. The project intends to continue research and development of DTI through in-vivo and in-vitro experimental studies to demonstrate prostate tumorigenesis is inhibited by chemical or surgical sympathectomy and genetic disruption of adrenergic receptors, to demonstrate prostate cancer invasion and metastasis are prevented by pharmacological blockade or genetic deletion of muscarinic receptor, to analyze the relationship between the densities of sympathetic and parasympathetic nerve fibers in tumor and prostate cancer aggressiveness, and clarify the effects of the use b-blocker propranolol on sympathetic nerve fibers and pirenzepine on parasympathetic nerve fibers in men with prostate cancer, to reveal growth and progression mechanisms and potential therapeutic targets associated with PNI in prostate cancer, to provide new strategy for the prevention, and treatment of prostate cancer.

对前列腺癌生长和转移机制缺乏深入认识仍是我国前列腺癌死亡率显著上升的主要原因，为此，深入探讨前列腺癌神经周围侵犯PNI机制，找到潜在治疗靶点具有重要的理论意义和应用价值。在前列腺侵袭性的前期研究中，申请者运用磁共振DTI技术示踪前列腺癌病灶的纤维束，并阐明前列腺癌侵袭度，其FA、ADC与Gleason评分显著相关。该现象强烈提示DTI技术可能揭示前列腺癌的周围神经侵犯(PNI)机制及其潜在治疗靶点。为此，本项目拟通过体外和体内实验，运用磁共振DTI技术结合HE染色分析、免疫组化检测进一步分析化学或手术交感神经切除术和肾上腺素能受体基因删除阻止前列腺癌发生；毒蕈碱胆碱能受体拮抗剂和受体基因删除抑制前列腺癌发生进展和转移；蕈毒碱受体拮抗剂和肾上腺素受体阻滞剂防治前列腺癌转移的临床试验。从而达到识别前列腺癌的关键“靶点”、提供前列腺癌抗癌治疗依据。

前列腺癌的神经密度与前列腺癌的侵袭性和预后相关。然而，到目前为止，还没有开发出理想的可视化方法来评估活体前列腺癌的神经密度。研究人员利用超顺磁性氧化铁纳米颗粒和神经多肽，负载神经受体阻断剂普萘洛尔，合成了能特异性靶向前列腺癌神经的探针，PSN NPs。PSN NPs 可以通过磁共振成像（MRI）和磁性粒子成像（MPI）评估前列腺癌的神经密度和侵袭性，实现了高灵敏度和高特异性的前列腺癌神经密度可视化。此外，PSN NPs 还可以靶向 阻断前列腺癌的神经功能，抑制前列腺癌进展。数据显示，与对照组相比，PSN NPs 使原位前列腺癌小鼠的存活率提高到83.3％，肿瘤神经密度和增殖指数降低2倍以上。该研究为临床前列腺癌神经的成像和治疗提供了潜在的依据，为前列腺癌的精准诊疗提供了新策略。