SDF-1-Leptin信号环在前列腺癌-脂肪微环境中促进肿瘤快速演进作用机制的研究

Prostate adenocarcinoma is one of most common solid malignancies in male. Relapse and metastasis of prostate adenocarcinoma is predominately associated with poor prognosis. Unfortunately, till know, the accurate molecular mechanism trigging relapse and metastasis in prostate adenocarcinoma is thoroughly unknown. Recently, several studies began to focus on the association of adipocytes with tumor progression in a few solid tumor types. The role of tumor-adipocyte microenvironment in rapid progression of prostate adenocarcinoma is absolutely obscure. In our previously study, rapid progression of prostate adenocarcinoma seemed to be initiated by a new signal loop (SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1 axis) within prostate adenocarcinoma-adipocyte microenvironment. Based on these results mentioned above, we prospected to confirm this pivotal signaling loop in tumor relapse, metastasis and resistance and further illuminate the precise molecular mechanism with diverse methods and techniques. SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1 axis would be expected to be one of novel and promising targets in reversing relapse, metastasis and drug resistance in patients with prostate cancer.

前列腺癌是男性最常见的恶性实体肿瘤之一。前列腺癌复发、转移是影响患者生存的重要危险因素。目前，对于前列腺癌复发及转移的分子机制研究欠清。最近研究发现在肿瘤微环境中的脂肪细胞是导致肿瘤复发和转移的重要因素，但前列腺肿瘤--脂肪细胞的相互作用是否参与肿瘤快速演进及药物抵抗，目前仍不清楚。结合国外相关研究，本课题前期通过基因芯片、定量PCR、蛋白印迹等研究提示：前列腺肿瘤--脂肪细胞间可能通过SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1信号环路启动前列腺癌快速演进。本课题拟运用多种实验技术，证实SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1信号环路是导致前列腺癌复发、转移及肿瘤耐药的重要信号通路，并阐明该信号通路介导肿瘤细胞增殖、迁移、侵袭及药物抵抗的具体分子机制，最终可能为前列腺癌复发、转移及药物抵抗的治疗提供新思路。

前列腺癌是男性最常见的恶性实体肿瘤之一。前列腺癌复发、转移是影响患者生存的重要危险因素。目前，对于前列腺癌复发及转移的分子机制研究欠清。最近研究发现在肿瘤微环境中的脂肪细胞是导致肿瘤复发和转移的重要因素，但前列腺肿瘤--脂肪细胞的相互作用是否参与肿瘤快速演进及药物抵抗，目前仍不清楚。本课题通过多种技术手段结合体内、外研究证实：前列腺肿瘤-脂肪细胞间可通过SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1信号环路启动前列腺癌快速演进。本研究发现：前列腺肿瘤细胞能通过SDF-1/CXCR4信号通路诱导脂肪细胞Leptin表达。脂肪细胞分泌的外源性Leptin进一步通过ZEB1、Twist-1等相关转录因子，启动前列腺癌细胞的恶性转变，同时诱导肿瘤细胞持续性表达SDF-1，从而在前列腺肿瘤-脂肪细胞间形成SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1这一恶性循环，最终诱导肿瘤快速演进并参与药物抵抗的发生。通过药物阻断这一恶性循环中的关键分子，则可以有效抑制肿瘤细胞的恶性进展和药物抵抗。通过本课题的研究，揭示了肿瘤-脂肪微环境中SDF-1-Leptin-ZEB1/Twist-1-CXCR4/SDF-1信号环路介导前列腺癌复发、转移及肿瘤耐药的重要机制，最终可能为前列腺癌复发、转移及药物抵抗的治疗提供新思路。