一氧化氮促进肿瘤基质干细胞形成肺癌转移前龛的机制研究

Bone marrow derived mesenchymal stem cells are capable of differentiating and homing to tumor sites. They are the main component of tumor microenvironment, termed as cancer stromal stem cells. It has been reported that cancer educated stromal stem cells form a permissive pre-metastatic niche at distant sites for cancer cells and promote the metastasis of cancer cells. The mechanisms of pre-metastatic niche initiated by cancer stromal stem cells remain to be elucidated. Our previous work showed that nitric oxide in the tumor microenvironment promoted the invasion and metastasis of cancer cells by cytoskeletal remodeling, which was induced by cytoskeleton regulated protein caldesmon complexed with myosin and src substrate cortactin. The aim of this project is to dissect the roles of nitric oxide in the mobility of cancer stromal cells and establishment of pre-metastatic niche.In this project, we are going to investigate: 1. the mechanisms of enhanced mobility of cancer stromal stem cells by nitric oxide; 2. the relationship of mobility of cancer stromal stem cells and establishment of pre-metastatic niche;3. the mechanisms of cancer stromal stem cell promoting metastasis of lung cancer cells by forming pre-metastatic niche.The proposed research is significant because by revealing the initial steps of metastasis of cancer cells,targets can be selected for future treatment to interrupt the process of metastasis at early stage.

骨髓来源间充质干细胞具有分化潜能和向肿瘤部位移动的能力，是肿瘤微环境的重要组成成分，被称为肿瘤基质干细胞。研究表明肿瘤环境下的基质干细胞可在远处组织形成转移前龛，提供适应肿瘤细胞生存的微环境，促进肿瘤细胞的侵袭转移过程。肿瘤基质干细胞形成转移前龛的分子机制目前还不明确。我们的前期研究表明在肿瘤微环境下一氧化氮能促进细胞骨架调节蛋白caldesmon和肌球蛋白、Src substrate cortactin形成复合物，导致细胞骨架重塑，促进细胞运动迁移能力。本项目以肺癌为研究模型，从以下几个方面探讨一氧化氮促进肿瘤基质干细胞的运动能力，并形成转移前龛的假说:1.一氧化氮促进肿瘤基质干细胞运动能力的分子机制；2.肿瘤基质干细胞的运动能力与转移前龛形成的关系；3.肿瘤基质干细胞通过形成转移前龛促进肺癌细胞侵袭转移能力的机制。本项目的实施将为阐明肿瘤转移的早期步骤以及早期阻断转移过程提供理论依据。

肿瘤微环境在肿瘤转移中发挥重要作用。骨髓来源间充质干细胞具有分化潜能和向肿瘤部位移动的能力，是肿瘤微环境的重要组成成分，被称为肿瘤基质干细胞。研究表明肿瘤基质干细胞可在远处组织形成转移前龛，提供适应肿瘤细胞生存的微环境，促进肿瘤细胞的侵袭转移能力。肿瘤基质干细胞形成转移前龛的分子机制目前还不明确。我们的研究表明肿瘤基质干细胞在肿瘤细胞的影响下发生表型和基因表达谱的差异，在肿瘤微环境下，肿瘤基质干细胞一氧化氮合酶表达明显增高，一氧化氮合酶在基质干细胞内促进细胞骨架调节蛋白caldesmon和src substrate cortactin形成复合物，导致细胞骨架重塑，促进基质干细胞的运动能力。肿瘤基质干细胞从肿瘤部位向外周血循环播散，在骨髓部位定居。肿瘤基质干细胞在播散的过程中，细胞表型和基因表达谱进一步发生变化，CXCL5, iNOS, GM-CSF等免疫抑制分子表达明显上调，从而在骨髓部位促进髓性抑制细胞（MDSC）Ly6G阳性细胞的扩增。Ly6G阳性细胞在骨髓中通过抑制T细胞的活性，从而形成免疫抑制环境，从而促进肿瘤细胞在骨髓部位的生存。而应用CXCL5抗体，iNOS抑制剂1400W, GM-CSF抗体可以提高PD-L1抗体的抗肿瘤效果，延长荷瘤小鼠的生存时间。本项目的实施将为早期阻断转移过程提供理论依据。