GDF-15/TGF-β恶性正反馈环路在介导肿瘤微环境参与乳腺癌侵袭转移中的作用及机制研究

Breast cancer is the common female cancer and although many advanced treatments have resulted from improving clinical instruments and methods, metastasis still leads to cancer mortality and and poor prognosis. It has been reported that Tumor-associated macrophages (TAMs), the most abundant immune-related stromal cells in tumor microenvironment, directly affected immunosuppression, neoangiogenesis, and exerted a significant effect on metastasis. Our previously results indicate that TAMs are frequently observed at the invasive front of advanced tumors, where GDF-15, a divergent member of the transforming growth factor beta super-family, is usually found to be increased. Moreover, we revealed that GDF-15 from mesenchymal-like breast cancer cells could activate TAMs to secrete TGF-β abundantly and that TGF-β from TAMs, in turn, could stimulate tumor cells’mesenchymal transition and secreting GDF-15 abundantly. In line with the given results, we suggest that cancer cells at the invasive front of the tumor tissue could interact with TAMs through GDF-15 and TGF-β, forming a malignant posive feedback loop in tumor microenvironment, to promote breast cancer metastasis and invasiveness. Based on the results of preliminary experiment and literature research, in this study, we aimed to investigate the contribution of the malignant posive feedback loop in breast cancer metastasis in vitro and in vivo, combined with clinical studies, and to identify its molecular mechanism. Our study might extend the knowledge of mechanism of tumor metastasis and of the interaction between cancer cells and TAMs, and might also provide a potential therapeutic target for clinic therapy of breast cancer metastasis in future.

乳腺癌严重威胁着女性的生命和健康, 肿瘤转移是影响乳腺癌患者生存期的最主要原因。研究发现，肿瘤相关巨噬细胞（TAM）参与肿瘤的免疫逃逸、血管生成等过程；尤其在肿瘤的侵袭转移过程中发挥重要作用。我们前期研究发现：在乳腺癌组织侵袭前沿部位GDF-15和TAM的浸润明显增多，且与肿瘤侵袭转移密切相关；GDF-15体外能诱导TAM分泌TGF-β；TGF-β能够诱导间质化的肿瘤细胞分泌GDF-15。因此，我们提出假说：乳腺癌组织侵袭前沿的间质样肿瘤细胞与TAM通过分泌GDF-15/TGF-β形成恶性正反馈环路，造成局部肿瘤转移微环境，加剧肿瘤细胞的侵袭转移。本项目拟在前期研究基础上，通过体内体外实验结合临床样本分析系统阐明该恶性环路在乳腺癌侵袭转移中的重要作用并探讨其中的关键分子机制。本课题通过肿瘤细胞与TAM相互作用形成的肿瘤转移微环境的研究，为乳腺癌侵袭转移提供新机理，也为其治疗提供新思路。

乳腺癌严重威胁着女性的生命和健康, 肿瘤转移是影响乳腺癌患者生存期的最主要原因。研究发现，肿瘤相关巨噬细胞（TAM）参与肿瘤的免疫逃逸、血管生成等过程；尤其在肿瘤的侵袭转移过程中发挥重要作用。本课题在前期研究的基础上提出假说：乳腺癌组织侵袭前沿的间质样肿瘤细胞与TAM通过分泌GDF-15/TGF-β形成恶性正反馈环路，造成局部肿瘤转移微环境，加剧肿瘤细胞的侵袭转移。我们从临床样本、体内实验，体外细胞行为学实验三个层面系统验证了乳腺癌组织中的间质样肿瘤细胞与肿瘤相关巨噬细胞之间存在由 GDF15/TGF-β形成的正反馈恶性环路及其对肿瘤侵袭转移的促进作用；并通过一系列细胞学和分子生物学实验证实GDF15既可通过激活K-Ras→JNK →Stat3 →c-Myc通路，从转录水平调控c-Myc，又可通过激活K-Ras→ ERK→ c-Myc通路，以蛋白修饰的方式稳定c-Myc，进而调控TGF-β1表达的分子机制；初步探讨了乳腺癌细胞中TGF-β通过启动子直接上调GDF-15的分子机制。本课题通过间质样肿瘤细胞与肿瘤相关巨噬细胞相互作用形成的肿瘤转移微环境的研究，为乳腺癌侵袭转移提供新机理，也为肿瘤转移治疗提供新思路与新靶点。