肺癌微小转移癌微环境多模态研究

Lung cancer accounts for 29% cancer deaths worldwide, although systemic chemotherapies and radiotherapy are generally given after surgical remove of primary lung cancer the overall long-term survival has not be significantly improved. Metastases, especially micrometastases, of lung cancer may be the major reason for lung cancer death, the efficacy of systemic treatments of the micrometastatic disease may be compromised by hypoxic resistance. 18F-FMISO (or 124I-IAZGP) and 18F-FDG Micro-PET / CT were used to detect the hypoxia of metastatic carcinoma and the dynamic changes of hypoxia during the process of metastatic carcinoma.In this study,we shall use metastatic models to seek further understanding hypoxia, its relation to angiogenesis and other microenvironmental factors in lung cancer metastases. We will establish nude mice model of multiple organ metastases of lung cancer cells. We shall then visualize hypoxia, in varying size of metastases, and explore whether these features are location dependent using invasive immunohistochemistry.and noninvasive molecular imaging techniques. And we shall also observe change in.hypoxia during early stage of development of micrometastases using molecular imaging techniques. If our hypothesis is proved to be true, our findings will guide the development of novel hypoxia targeted new therapeutic strategy to treat micrometastases and novel early detection techniques, prolong long term survival and possibly result a cure of the deadly disease.

研究表明肺癌占所有的癌症导致的死亡的29%，目前切除原发灶并放疗、化疗、生物治疗等各种辅助治疗并没有从根本上改善肺癌患者的整体生存率，肺癌微小转移癌被认为是主要原因，而乏氧可能是微小转移癌对辅助治疗产生耐受的机制。因而本研究拟建立肺癌细胞多器官鼠转移癌模型。应用18F-FMISO（或124I-IAZGP）和18F-FDG Micro-PET/CT 活体成像与光学成像相结合检测转移癌的乏氧情况及转移癌生长过程中乏氧的动态变化情况，研究不同部位的肺癌微小转移癌的乏氧状态，探讨不同解剖部位、不同时期的肺癌微小转移癌是否都具有高度乏氧这一共性特征及肺癌转移癌在早期发展过程中乏氧分布与血管新生和细胞增殖的关系；同时应用分子影像技术观察微小转移癌早期生长过程中乏氧的动态变化。通过上述研究结果指导临床研发新的乏氧靶向治疗方案和早期检测方法，提高肺癌患者生存率、实现根治肺癌的目的。

非小细胞肺癌是目前发病率和死亡率最高的疾病，切除原发灶放疗、化疗、生物治疗等各种辅助治疗并没有从根本上改善肺癌患者的整体生存率，而肿瘤微环境中乏氧及肿瘤新生血管可能是转移癌对辅助治疗产生耐受及转移的机制。目前机制尚未明确，因而本研究建立肺癌细胞多器官转移癌模型。应用Micro-PET/CT活体成像与SPECT/CT相结合检测转移癌的乏氧情况、新生血管情况及转移癌生长过程中增殖情况；通过免疫荧光研究不同部位的肺转移癌的乏氧状态，新生血管状态，增殖状态极其空间关系，探讨不同解剖部位、不同时期的肺癌微小转移癌是否都具有高度乏氧这一共性特征及肺癌转移癌在发展过程中乏氧分布与血管新生和细胞增殖的关系。结果：1.研究证明高度乏氧是肺癌转移癌不同部位转移具有共同的特征。2.99mTc-3PRGD2-SPECT/CT及18F-FDG-micro-PET可作为无创的手段诊断肺癌的增殖、乏氧及新生血管情况。3.接近坏死区域的癌组织Pimonidazole、CA-9、HIF-1a表达阳性，EDU及CD31表达为阴性，表明坏死组织周围为乏氧区域无新生血管出现。在肿瘤的周围细胞增殖明显存在新生血管。4.Micro-PET的SUVmean值与肿瘤乏氧荧光强度成正相关，SPECT/CT的SUMmean值与微血管密度成正相关与肿瘤乏氧荧光强度成负相关。通过上述研究结果指导临床研发新的乏氧靶向治疗方案和早期检测方法，提高肺癌患者生存率、实现根治肺癌的目的。