间质干细胞（MSC）是肿瘤微环境的重要组分，肿瘤干细胞（CSC）是复发、转移的种子,二者相互依存，交互作用，但机制不清。前期研究表明结直肠癌（CRC）与MSC细胞共培养后，CSC表型增加, 趋化信号SDF-1/CXCR4上调；MSC高表达CD105,其配体TGF-β1在CRC中表达，且与预后密切相关。我们推测：TGF-β1结合CD105可能激活MSC，增强SDF-1/CXCR4信号轴，促进CSC自我更新及转移。本课题拟通过体外、体内MSC与CRC共培养体系，研究二者交互作用后细胞功能的改变，上述信号及相关分子的变化，探讨结直肠癌通过TGF－β1改变MSC，增强CSC与MSC交互作用的机制；最后联合分子阻断，实验同时靶向MSC及CSC在结直肠癌治疗中作用。本研究的实施可能为结直肠癌的整体防治提供新的理论基础和治疗策略

Recently, mesenchymal stem cells (MSC) were reported to migrated to tumor stroma and promote colorectal cancer cell proliferation and invasion by direct contact and/or soluble factors.And we know， only a few colorectal cancer cells, as named cancer stem cell,are responsible for disease relapse. We hypothesize that interaction between colorectal cancer stem cells and MSC play a key role in the tumorigenesis and metastasis of colorectal caner. Our data showed that chemokine axis of SDF-1/CXCR4 was elevated and percentage of CD133+ positive colorectal cancer cells increased during the co-cuture of MSC and colorectal cancer cells,so we propose a central role of SDF-1/CXCR4 axis for crosstalking between colorectal cancer stem cell and MSC，and maintaining stemness and function of colorectal cancer stem cell.Colorectal cancer cells also showed highly expression of TGF-β1, which significantly impacts progression and prognosis.And TGF-β1 is the ligand of CD105, which is highly expressed on MSCs. We proposed that TGF-β1 in the microenviroment activated MSCs and promote interaction between MSC and colorectal cancer stem cell through dysregulated SDF-1/CXCR4 signaling axis, which maintaining colorectal cancer cell stemness and proliferation, and then lead to tumor relapse. In this project, we will employ in vivo and in vitro co-culture system to depict the interaction between MSC and colorectal cancer/stem cells. Final results therefore provide evidence of a role for MSC in maintaining colorectal cancer stem cell through crosstalk between TGF-β1 and SDF-1/CXCR4 axis signaling pathway, which imply a new integrated strategy for treatment of colorectal cancer

肿瘤并不是一个单一的组织，是肿瘤细胞及其微环境的有机体。研究表明，肿瘤微环境在肿瘤的形成，生长以及扩散中起着至关重要的重要。MSC，肿瘤微环境中的重要一份子，近年来被发现在不同的肿瘤中可能起到不同的作用，但具体机制不明。因此本项目旨在从结直肠癌组织中分离出MSC，通过其与结直肠癌细胞共培养的方法观察MSC对结直肠癌的影响及其机制，以及在分子水平干预是否会使MSC对结直肠癌的影响减弱或消失，最后在体内模拟MSC对结直肠癌的影响是否仍然存在。在研究中，我们发现将MSC与结直肠癌细胞间接共培养后，结直肠癌细胞的增殖、侵袭转移能力明显增强，以及间接共培养后的结直肠癌细胞促进血管生成的能力也显著增强，除此在外，我们发现MSC可以在一定程度上帮助肿瘤细胞逃逸衰老，还可以增强结直肠癌细胞与血管的粘附能力。这说明在结直肠癌中，MSC有明显促进其进展的作用。接下来，我们研究了MSC产生这些效应的机制，我们发现MSC条件培养基中IL-6水平很高，处理结直肠癌细胞后IL-6/P-STAT3通路明显激活，在运用IL-6中和抗体或者STAT3抑制剂后，MSC促进结直肠癌细胞的增殖、侵袭转移能力明显减弱，同时，我们还发现MSC条件培养基可使结直肠癌细胞P53降解明显增多，进一步下调P21的表达，在重新转入P53高表达质粒后，MSC帮助肿瘤细胞逃逸衰老的能力基本消失，另外，我们发现MSC处理后的结直肠癌细胞VEGF-A表达量也明显增多，以及VCAM上膜和表达量均增多，这也就说明了MSC促进肿瘤成管及与血管粘附的可能机制。最后我们在裸鼠在体实验中同样也发现了MSC可以促进结直肠癌成瘤以及转移。综上所诉，MSC在结直肠癌的恶性发展中起到了推波助澜的作用，在今后的研究中或许可以发现一种靶向药物针对MSC，在早期肿瘤局部注射这种药物可以诱导MSC凋亡或者坏死，从而改善患者的预后。