肿瘤间质内压与淋巴管生成在肿瘤转移中作用机制的MR分子影像研究

Experimental and clinical studies have provided substantial evidence that highly elevated interstitial fluid pressure (IFP) and lymphangiogenesis in tumors is associated with tumor lymphatic metastasis. However, the relationship between these two factors and their impact on tumor metastasis has not been reported. Based on our previous research on contrast agent and MR imaging of the lymphatic system, we will use our newly developed, lymphatic-transported nano-particle, HA-Gd-DTPA, as a MR contrast agent to evaluate tumor IFP and tumor-induced lymphangiogenesis noninvasively in this project. After MR scanning, interstitial fluid pressure in tumor tissues was measured in vivo using a polyurethane transducer-tipped catheter (Millar). Subsequently, the tumor tissue and lymph nodes in the experimental animal will be dissected and fixed in formalin solution. A well-designed and optimized enzyme, immunohistochemical technique, will be applied to investigate the lymphangiogenesis in the tumor tissue and metastatic lymph nodes. Statistical analysis will be performed to determine the relationship between the tumor IFP, lymphangiogenesis, and lymphatic metastases. Thus, two pathological phenomena, high tumor IFP and lymphangiogenesis that associated with tumor lymphatic metastasis, which was completely separate evaluated will be consolidated to a dynamic continuous research process. On this basis, an accurate, reliable and sensitive MR protocol and data analysis method will be further built for the assessment of tumor IFP and tumor lymphangiogenesis. This study will open a new door to understanding tumor-induced interstitial hypertension and lymphangiogenesis, and elaborate the underlying mechanisms of tumor IFP, tumor lymphangiogenesis and lymphatic metastasis. If successful, we will not only create a novel approach for tumor staging, treatment and prognosis assessment, but also obtain in vivo imaging methods for evaluating tumor IFP and lymphangiogenesis in lymphatic metastasis for the first time.

研究表明，肿瘤发生淋巴转移与肿瘤间质内压（Interstitial Fluid Pressure, IFP）升高及肿瘤淋巴管生成有关，但两者之间相互作用机制及对肿瘤转移的影响未见报道。本课题在前期研究淋巴系统成像的基础上，运用淋巴系统特异转运造影剂HA-Gd-DTPA通过无创分子影像和功能影像的方法同时获得对转移性与非转移性肿瘤的IFP及肿瘤淋巴管生成情况的评估，并与活体实测肿瘤IFP及病理获得的肿瘤淋巴管表现相对照，分析肿瘤IFP-淋巴管生成-淋巴微转移之间的时间关系、先后关系和量级关系，从而将肿瘤IFP升高与淋巴管生成两个截然分开的病理现象变成一个连续、统一、动态的研究过程；并进一步建立对肿瘤IFP与肿瘤淋巴管可靠评估的MR分子成像技术及解析方法。本研究将更加全面直观地揭示肿瘤淋巴转移中相关因素的作用及其机制,为肿瘤淋巴转移机制研究和临床开展无创评估肿瘤IFP及淋巴管生成提供新的手段。

肿瘤发生淋巴转移与肿瘤间质内压（Interstitial Fluid Pressure, IFP）升高及肿瘤淋巴管转移有关，本课题在前期研究淋巴系统成像的基础上，运用淋巴系统特异转运造影剂HA-Gd-DTPA 通过无创分子影像和功能影像的方法同时获得对转移性与非转移性肿瘤的IFP及肿瘤淋巴管生成情况的评估，并与活体实测肿瘤IFP 及病理获得的肿瘤淋巴管表现相对照，分析肿瘤IFP-淋巴管生成-淋巴微转移之间的时间关系、先后关系和量级关系，从而将肿瘤IFP 升高与淋巴管生成两个截然分开的病理现象变成一个连续、统一、动态的研究过程；并进一步建立对肿瘤IFP 与肿瘤淋巴管可靠评估的MR 分子成像技术及解析方法。本项目运用材料学、药物合成、分子影像学、分子生物学及免疫组织化学等多个跨学科技术开展不同分子量透明质酸（Hyaluronic acid）为载体的MR造影剂HA-Gd-DTPA的合成，具有良好的生物安全性，并且稳定、安全、驰豫性能好，不同分子量的对比剂的成功合成也提供了探索不同分子量对比剂在肿瘤内生物效应的途径。在肿瘤IFP评估中，显示不同分子量对比剂均可用于IFP评估，30~40kDa拥有更好的表现。IFP可能是驱动肿瘤淋巴结转移的原始物理动力，且通过合适的对比剂选择可以更好评估肿瘤淋巴结概率，为将来进一步研究IFP在肿瘤发生发展过程中的价值提供活体研究平台。