结直肠癌在肿瘤中发病率和死亡率均位居第三，其复发、转移和耐药已经成为临床治疗的主要问题。近年来研究表明，尽管不同治疗方式下耐药产生的机制各异，由多种治疗手段引起肿瘤组织损伤和炎症共同介导的肿瘤微环境的改变是肿瘤耐药产生的主要原因之一。本课题组的前期研究发现促炎因子GM-CSF长期刺激可诱导结直肠癌细胞对化疗药（5-FU、奥沙利铂和伊立替康）不敏感，并促进了肿瘤细胞的迁移和侵袭。据此，我们提出如下科学假设：肠道肿瘤微环境中GM-CSF的过量分泌有可能通过上皮-间质转化（EMT）和髓系来源抑制性细胞（MDSC）诱导分化等途径参与了结直肠癌的转移和耐药。本项目拟采用生物化学和分子生物学方法在细胞水平、动物模型和临床患者标本多个层面论证我们的假说。本课题研究不仅将有助于阐明GM-CSF介导结直肠癌转移和耐药的分子机制，而且为进一步靶向肿瘤微环境治疗肿瘤耐药提供新的思路。

Colorectal cancer has the third leading incidence and mortality rate among human tumors. Tumor relapse, metastasis and drug resistance remain the main obstacle to the success of cancer treatments. Recent reports have revealed that although the mechanism of diverse therapies varies, alteration of tumor microenvironment in response to therapy-induced tumour tissue injury and inflammation contributes to the development of drug resistance. Our preliminary results showed that chronically stimulated GM-CSF can induce the drug resistance to chemotherapeutic drug (e.g. 5-FU, oxaliplatin and irinotecan) and promotes tumor cells invasion and migration in colorectal cancer cell lines. Therefore, we hypothesize that an excess secretion of GM-CSF in microenvironment may facilitate tumor metastasis and drug resistance mainly via epithelial-to- mesenchymal transition (EMT), myeloid-derived suppressor cells (MDSC) induction. In the present study, we will conduct the experiments in vitro, in vivo and clinical sample level by means of general biochemical and molecular biology methods, and finally demonstrate our hypothesis. Therefore, our study will not only clarify the molecular mechanisms of GM-CSF mediated metastasis and drug resistance in colorectal cancer, but also accelerate development of reversal agents for the treatment of microenvironment-mediated drug resistant human tumors.