结直肠癌常发生远处转移，严重影响预后，其调控机制仍不清楚。β淀粉样蛋白（Aβ）由其前体蛋白APP被β分泌酶（BACE-1）及其它分泌酶剪切而来，可沉积在血管壁上诱导脑血管功能障碍，但与肿瘤转移和预后的关系尚未见报道。申请人在青年项目支持下，发现APP及BACE-1在结直肠癌中高表达，且Aβ沉积在血管内皮及壁细胞上所诱导的凋亡与转移密切相关。进一步发现：二甲双胍通过下调Aβ生成，抑制血管成分细胞凋亡诱导的远处转移，潜在机制与显著被下调的BACE-1表达水平有关。基于此首次提出假说：二甲双胍可能通过下调BACE-1抑制Aβ生成及在血管壁上的沉积，进而抑制血管内皮及壁细胞凋亡介导的结直肠癌血行转移？我们拟通过标本分析及体内外实验，阐明结直肠癌细胞通过生成Aβ诱导血管成分细胞凋亡的机制，及证实二甲双胍通过影响BACE-1/Aβ生成通路所发挥的血管保护性作用，为抗结直肠癌转移提供新的靶点及思路。

Distant metastasis can be commonly found in patientis with colorectal cancers, and greatly affects the prognosis of patients. However, the underlying molecular mechanisms remain unclear. Amyloid β (Aβ) is cleaved from its procusur protein APP by β secretase (BACE-1) and other secretases, which deposits on vascular wall and induces vascular dysfunction. However, its relationship with tumor metastasis and prognosis has not yet been reported. The applicant was supported by the youth program of ISIS, and found that APP and BACE-1 were highly expressed in CRCs. In addition, Aβ deposition-induced apoptosis of vascular endothelial and mural cells was closely associated with the distant metastasis. Basing on an orthotopic model, we further found that metformin reduced the production of Aβ and inhibited apoptosis of vascular component cells and distant metastasis, and the underlying mechanism was associated with decreased BACE-1 expression level. Basing on those evidences, therefore, we first assume that metformin inhibited Aβ production and the deposition on vascular wall by downregulation of BACE-1, thus restraining the apoptosis of vascular endothelial and mural cells-induced CRCs distant metastasis. We intend to perform clinical, in vitro and in vivo experiments for elucidating the mechanism that CRCs induces vascular component cells apoptosis, and verifying the effects of metformin on vascular protection via suppression of BACE-1/Aβ production pathway. These efforts and the expected results will provide new targets and ideas for treatment of CRCs.