胰腺癌因其恶性程度和病死率高等特点已成为严重威胁我国人民健康的一种恶性疾病。在众多发病原因中，慢性胰腺炎诱发胰腺癌的可能性引起越来越多的关注。白血病抑制因子（LIF）在炎症过程中产生，可诱导单核细胞向肿瘤相关巨噬细胞转化，促进肿瘤细胞和肿瘤干细胞增殖，可能是炎癌转化的关键因子。我们前期应用组织芯片的结果表明LIF在正常人胰腺组织中表达呈阴性，在慢性胰腺炎组织中表达呈阳性，并且在胰腺癌组织中表达量明显高于癌旁正常组织；提示其在胰腺炎癌转化过程中发挥作用。本项目拟通过体外细胞共培养方法，研究LIF在胰腺炎癌转化过程中的调控机制，利用胰腺炎癌转化动物模型，检测随病变进程LIF表达情况并对其表达进行干扰，明确LIF在胰腺炎癌转化中的作用；最后应用LIF中和抗体在人源肿瘤移植小鼠模型中评估拮抗LIF对胰腺癌治疗的意义。为探讨LIF作为胰腺癌治疗靶点、开发LIF中和抗体药物奠定基础。

Pancreatic cancer is considered as a highly lethal malignancy, which is already threatened people’s health in our country. Among the many risk factors for pancreatic cancer, chronic pancreatitis had been attracted more and more attentions recently. Leukemia inhibitory factor (LIF) could be induced during inflammation and was capable of inducing the polarization from monocytes to tumor-associated macrophages. It was also suggested LIF could promote the proliferation both of the cancer cells and the cancer stem cells. Thus LIF might function as a novel regulator in promoting the transition from inflammation to cancer. By using tissue microarray technology, the expression of LIF was observed to be negative in normal human pancreatic tissues and positive in human pancreatitis tissues. Meanwhile, it was also observed that LIF expression was significantly increased in human pancreatic cancer tissues as compared to that in the adjacent non-tumor tissues. All the above results suggested that LIF might be involved in the transition from pancreatitis to pancreatic cancer. In this study, the in-vitro co-culture method will be used to investigate the regulation mechanism of LIF during the transition from pancreatitis to pancreatic cancer. And the animal model of pancreatitis to pancreatic cancer will also be used. The primary task of this study will be to observe the expression changes of LIF and use interventions to antagonize the function of LIF during the transition from pancreatitis to pancreatic cancer. Results will be used to clarify the impact of LIF expression during this transition. The patient-derived xenograft (PDX) mouse model will also be used to evaluate the efficacy of LIF neutralizing antibody for the treatment of pancreatic cancer. This study will have the potential to develop LIF as a treatment target for pancreatic cancer disease and will lay foundation for developing LIF neutralizing antibody as a novel drug for pancreatic cancer patients.

胰腺癌因其恶性程度和病死率高等特点已成为严重威胁我国人民健康的一种恶性疾病。在众多发病原因中，慢性胰腺炎诱发胰腺癌的可能性引起越来越多的关注。白血病抑制因子（LIF）在炎症过程中产生，可诱导单核细胞向肿瘤相关巨噬细胞转化，促进肿瘤细胞和肿瘤干细胞增殖，可能是炎癌转化的关键因子。本项目在过去的一年中主要围绕白血病抑制因子在胰腺炎癌转化中的调控机制这一科学问题，首先应用生物信息学和组织芯片等方法，分析了胰腺癌组织和癌旁组织中LIF和LIF受体（LIFR）的表达情况，结果提示LIF在胰腺癌组织中的表达水平要高于癌旁正常组织，而LIFR在胰腺癌组织中的表达水平要低于癌旁正常组织，之后我们又应用TCGA数据库进行了生存分析，结果提示LIFR的表达水平同病人的预后具有相关性。为进一步研究LIF在胰腺癌发生发展中的作用，我们备了可以中和LIF活性的单克隆抗体，并建立和完善了一种重组LIF蛋白的表达和纯化方法，通过在培养的胰腺癌细胞中添加外源性LIF蛋白，研究发现LIF可促进胰腺癌细胞增殖和迁移，并且在对胰腺癌细胞成球培养的过程中，LIF/LIFR表达水平明显增高，特别在KRAS突变型的成球细胞中LIFR的表达水平上调更为明显，提示LIF/LIFR可能对于调控胰腺肿瘤干细胞的增殖具有重要的意义，LIF可能通过胰腺肿瘤干细胞的增殖增强胰腺癌的耐药性以及影响病人的预后，阻断LIF很可能改善胰腺癌病人的预后。