Periostin蛋白在乳腺癌转移前微环境中的功能及作用机制

Periostin is overexpressed in various human cancers such as breast cancer, and the overexpression of periostin is correlated with breast tumor metastasis. However, it is still unknown whether periostin is involved in the formation of pre-metastatic niche of breast tumor metastasis. Our data showed that periostin promotes the epithelial-mesenchymal transition in human mammary epithelial cells and breast cancer cells and endows these cells with stem cell-like properties. Periostin-overexpressed human mammary epithelial cells enhance the tumorigenetic capability of breast cancer cells and their lung metastasis. Conditioned medium of the periostin-overexpressed breast cancer cells injected intraperitoneally increases the levels of LOX and Fibronectin in the mice lung bronchiolus terminalis and recruits more CD11b+Gr1+ MDSCs into the mice lung tissues. These data demonstrated that periostin may contribute to the formation of pre-metastatic niche of breast tumor metastasis. On the basis of our previous studies about the roles of periostin in tumorigenesis and metastasis of breast cancer,this project will apply the periostin knockout mouse and MMTV-PyMT mouse models to investigate the functions and mechanisms of periostin in the pre-metastatic niche of breast tumor. This study will help us learn more about the functions of periostin in breast tumor metastasis and provide clues and a new target to the prevention and therapeutic intervention against latent and active tumor metastatic diseases.

Periostin蛋白在人乳腺癌等肿瘤组织中高表达，并与乳腺癌转移密切相关，但目前对其是否参与乳腺癌转移前微环境的形成并不清楚。我们的研究结果显示，Periostin可促进人乳腺上皮细胞和乳腺癌细胞发生EMT转分化并获得干细胞干性特征；高表达Periostin的人乳腺上皮细胞可促进乳腺癌细胞的成瘤和肺转移；连续腹腔注射高表达该蛋白的人乳腺癌细胞上清可促进肺部支气管末端LOX、Fibronectin等蛋白高表达，并促进CD11b+Gr1+ MDSCs等细胞向肺部汇聚，初步表明Periostin蛋白可能参与了乳腺癌转移前微环境的形成。本项目将应用Periostin基因敲除小鼠、MMTV-PyMT小鼠等模型，研究Periostin蛋白在乳腺癌转移前微环境中的功能及作用机制，以进一步从转移前微环境角度阐明Periostin在乳腺癌转移中的功能，并为肿瘤转移早期预防及治疗提供理论依据和新的作用靶点。

Periostin蛋白促进乳腺癌转移，是乳腺癌肺转移的关键限制性的肿瘤转移微环境因子，但对Periostin是否参与乳腺癌转移前微环境的形成并不清楚。该项目主要应用MMTV-PyMT乳腺癌自发性肺转移模型和Periostin敲除小鼠模型研究Periostin在乳腺癌转移前微环境中的功能及作用机制。我们的研究显示：（1）Periostin在乳腺癌肺转移前微环境中高表达；（2）Periostin促进骨髓来源的MDSC细胞在在乳腺癌肿瘤细胞到达肺部之前大量募集到小鼠肺部以及LOX氧化酶在肺部的活化；（3）敲除Periostin可明显抑制荷瘤小鼠肺组织中的MDSC细胞的募集以及LOX的活化；（4）敲除Periostin可通过抑制荷瘤小鼠MDSC细胞的Erk、Akt、STAT3信号通路激活来抑制MDSC细胞的免疫抑制功能，从而抑制免疫抑制性的肺转移前微环境的形成，抑制乳腺癌肺转移；（5）另外，Periostin还可通过增加乳腺组织硬度来促进乳腺癌细胞的侵袭转移。该研究是国际上第一个阐明Periostin是一种全新的肿瘤转移前微环境因子，对进一步阐明Periostin促进乳腺癌转移的机制具有重要意义，也为肿瘤转移早期防治提供了理论依据和新的作用靶点。