瑞香狼毒黄酮类活性成分通过调节TGF-beta-Smad2/3通路抑制肿瘤侵袭转移的功能及分子机制研究

Cancer invasion and metastasis represents the major problem in cancer treatment clinically and experimentally.It is also a crucial determinant for the survival of cancer patients.Through recent studies, it is widely accepted that TGF-beta-Smad2/3 signal pathway plays key role in the regulation of Epithelial-Mesenchymal Transition(EMT) and metastasis procedures. However, the research and development of new drugs targeting cancer metastasis has attracted little attention. It has long been recorded that Stellera chamaejasme L. can been used for anti-cancer treatment in the history of chinese medicine. However，its clinical application is largely limited due to its high cytotoxicity against normal cells.Our previous study has clearly identified the anti-tumor effects for the extracts from Stellera chamaejasme L.(ESC) in various kinds of tumor types. Interestingly, low-dose Stellera chamaejasme L. flavonoids also play key roles in the inhibition of TGF-beta-Smad2/3 pathway and EMT for cancer cells. Based on this indication, we plan to fully test the activity of Stellera chamaejasme L.flavonoids in cancer EMT regulation and metastasis inhibition. We will further reveal its molecular targets and the potential mechanism of ESC during the regulation of TGF-beta-Smad2/3 pathway in cancer cells. Our study will be helpful for the clear understanding of ESC activity for cancer treatment pharmacologically, and provide basic evidence for the research and development of anti-tumor drugs in clinical practice.

肿瘤侵袭和转移是医学关注和研究的重大科学问题，同时也是肿瘤患者生存的决定要素。近年研究证明，肿瘤的上皮间质变迁是调节肿瘤运动、侵袭及转移的核心机制，而TGF-beta/Smads通路是调控肿瘤EMT的核心通路。但与肿瘤转移的机制研究相比，以其为干预靶点的药物较少。狼毒抗癌自古便有记载，但其高毒性限制了其临床应用。本课题前期研究表明，瑞香狼毒提取物具有多样的抗癌功效，特别是黄酮类组分在低浓度下对肿瘤TGFbeta-Smad2/3通路具有明确的抑制作用，继而功能性的抑制肿瘤运动、迁移能力。本课题拟通过分子药理学等研究方法,进一步确证其在较低浓度下对肿瘤EMT和侵袭转移的抑制作用，分析其调节EMT活性的动力学特征，揭示其影响TGF-beta-Smad2/3通路的分子机制。本研究将拓展对瑞香狼毒抗癌机制的认识，并为肿瘤抗转移药物的研发提供基础研究证据，具有药理研究和临床应用的双重价值。

本项目研究在国家自然科学基金青年基金的资助下，立足临床实际应用，着重从解决抗肿瘤转移治疗的薄弱环节及瑞香狼毒抗癌应用的瓶颈问题出发，以肿瘤微环境中TGF功能悖论和平衡调节为理论立足点，以乳腺癌抗转移药物研发为宗旨。通过药物筛选、药效评价和分子药理学研究证明：瑞香狼毒黄酮类提取物ESC及其中的黄酮化合物狼毒宁B（ICJ）在低毒、低剂量范围内，能够以转化生长因子（Transformaing Growth Factor-β，TGFβ）“抗癌-促癌”平衡的分子开关ITGB3为作用靶点，通过选择性调控下游“Smad2/3”和“TβRII-FAK-Src-p38”TGF相关通路，纠正TGF在乳腺癌微环境中病理性的失衡状态，阻断肿瘤细胞上皮间质转分化进程，并进一步在药效水平，抑制肿瘤运动-侵袭-转移，有效延长荷瘤小鼠的生存期。同时，在拓展研究中，我们还发现瑞香狼毒还具有调节巨噬细胞极化平衡及肿瘤组织血管生成的潜在活性，定向诱导M1型极化，抑制肿瘤组织的血管新生，纠正微环境的促癌状态，形成转移药物干预的更广泛的时间窗，进一步支持了抗乳腺癌转移药效的高效发挥。.本研究，从肿瘤细胞和微环境的双重角度，将瑞香狼毒从高剂量、高毒性，肿瘤毒杀的靶点，转移至低剂量、低毒性，肿瘤转移的靶点，通过创新的药效评价，为突破自古以来瑞香狼毒临床应用的瓶颈提示了有效途径，为未来狼毒的抗乳腺癌新药研发奠定了实验研究基础；同时，还初步描述了瑞香狼毒抗肿瘤“多靶点、网络化、平衡调节”的模式，支持了中医药抗肿瘤的先进性和科学性，并为临床抗肿瘤转移治疗提供了有效可行的、具有中药特色的解决方案。