人胚胎干细胞分化的间充质干细胞调节人源性结肠癌异种移植物存活和生长的研究

As compared to traditional cancer cell line established tumor xenograft, patient derived tumor xenograft (PDX) is more appropriate for preclinical anti-cancer drug evaluation and personalized medicine strategies. However, low efficiency of engraftment and much slow growth of xenograft restrict widespread application of PDX. Our objective of this research is to overcome this disadvantage. Mesenchymal stem cell (MSC) and other stromal cell constitute tumor microenvironment to promote tumor initiation and progression. We found that co-administration colon cancer cell line with TMSC, which derived from human pluripotent stem cell through a trophoblast intermediate step, promote xenograft growth in immunodeficient mice. Co-administration with TMSC may promote patient derived colon cancer xenograft growth and increase efficiency of engraftment rate. The self-renewal and pluripotency properties of hPSC make it possible to generate infinite TMSC; We will stably overexpress tumor promoting factors IL6, VEGF and immunosuppression factor IDO1 in TMSC, to enhance their functions of tumor promoting and anti-NK cell toxicity, further to promote xenograft growth and efficiency of engraftment rate. If succeed, it will vastly shorten the period of establishment of human cancer biobank, and save cost and time for screening anti-cancer drug and personalized medicine strategies.

人源性肿瘤异种移植模型(PDX)能反映原代肿瘤特性，利于筛选潜在抗癌药物，但异种移植物存活率低和生长速度过慢，限制该模型广泛应用。间充质干细胞(MSC)参与组成肿瘤微环境促进肿瘤发生和发展。我们发现，人胚胎干细胞诱导分化的MSC (TMSC)和结肠癌细胞系共移植至NOD/SCID鼠显著促进肿瘤生长。据此推测，共移植TMSC很可能提高人源性结肠癌异种移植物存活率和加快肿瘤生长。人胚胎干细胞的无限自我更新能力为TMSC提供无尽来源；此外，将在TMSC稳定过表达促癌因子IL6、促血管发生因子VEGF以及免疫抑制因子IDO1，建立促肿瘤生长、促血管发生和拮抗NK细胞毒性能力更强的TMSC，进一步提高异种移植物在NOD/SCID鼠存活率和加速肿瘤生长；最后，将比较分析肿瘤异种移植物是否保持原代肿瘤异质性。该方法若成功，将极大缩短人源性肿瘤库建立周期，为抗肿瘤药物筛选和个性化治疗节约成本和时间。