胰腺星状细胞活化相关的信号转导通路

胰腺纤维化是慢性胰腺炎（chronic pancreatitis,CP）和胰腺癌主要的病理学特征,活化的胰腺星状细胞（pancreatic stellate cells,PSCs）是公认的致胰腺纤维化的主要效应细胞。PSCs的活化涉及到几个重要的信号转导通路：有丝分裂原活化蛋白激酶（mitogen-activated protein kinases,MAPK）、磷酯酰肌醇3激酶（phosphatidylinositol 3-kinase,PI3K）=、Smad信号转导蛋白、过氧化物酶体增生物激活受体-γ（PPAR-γ）、Rho-ROCK等细胞内信号途径。探讨这些信号通路在胰腺纤维化中所起的作用对慢性胰腺炎、胰腺癌及糖尿病的治疗有重要意义。现就与PSCs激活有关的信号通路的研究结合最新进展作一综述。     

Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer

Cancer must be viewed as a ‘tissue’, constituted of both transformed cells and a heterogeneous microenvironment, the ‘tumour microenvironment’ (TME). The TME undergoes a complex remodelling during the course of multistep tumourigenesis, hence strongly contributing to tumour progression. Ion channels and transporters (ICTs), being expressed on both tumour cells and in the different cellular components of the TME, are in a strategic position to sense and mediate signals arising from the TME. Often, this transmission is mediated by integrin adhesion receptors, which are the main cellular receptors capable of mediating cell-to-cell and cell-to-matrix bidirectional signalling. Integrins can often operate in conjunction with ICT because they can behave as functional partners of ICT proteins. The role of integrin receptors in the crosstalk between tumour cells and the TME is particularly relevant in the context of pancreatic cancer (PC), characterized by an overwhelming TME which actively contributes to therapy resistance. We discuss the possibility that this occurs through integrins and ICTs, which could be exploited as targets to overcome chemoresistance in PC.     

Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness

Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are characterized by extensive fibrosis. Importantly, in PDAC, this results in poor vascularization and impaired drug delivery to the cancer cells. Therefore, the combined targeting of pancreatic tumor stroma and chemotherapy should enhance response rates, but the negative outcome of a recent phase III clinical trial for the combination of chemotherapy and hedgehog pathway inhibition suggests that other means also need to be considered. Emerging data indicate that elimination of cancer stem cells as the root of the cancer is of pivotal importance for efficient treatment of pancreatic cancer. Recently, we demonstrated in a highly relevant preclinical mouse model for primary pancreatic cancers that the combination of cancer stem cell-targeting strategies in combination with a stroma-targeting agent, such as a hedgehog pathway inhibitor and chemotherapy, results in significantly enhanced long-term and progression-free survival. In the present study, we demonstrate mechanistically that Nodal-expressing pancreatic stellate cells are an important component of the tumor stroma for creating a paracrine niche for pancreatic cancer stem cells. Secretion of the embryonic morphogens Nodal/Activin by pancreatic stellate cells promoted in vitro sphere formation and invasiveness of pancreatic cancer stem cells in an Alk4-dependent manner. These data imply that the pancreatic cancer stem cell phenotype is promoted by paracrine Nodal/Activin signaling at the tumor-stroma interface. Therefore, targeting the tumor microenvironment is not only able to improve drug delivery but, even more importantly, destroys the cancer stem cell niche and, therefore, should be an integral part of cancer stem cell-based treatment strategies.     

雷公藤甲素诱导胰腺癌细胞凋亡

目的：观察雷公藤甲素对胰腺癌细胞BxPC-3和PANC-1生长抑制及诱导细胞凋亡作用,探讨雷公藤甲素抗胰腺癌的机制。方法：雷公藤甲素处理BxPC-3和PANC—1细胞后,用M1rr法检测细胞的生长抑制,用流式细胞术检测细胞的凋亡率,用罗丹明123和DCFH—DA染色方法测定细胞线粒体膜跨膜电位变化和活性氧（ROS）的产生,用Western印迹检测Bcl-2、Bax蛋白表达的变化。结果：雷公藤甲素对胰腺癌细胞BxPC-3和PANC—1具有生长抑制和诱导细胞凋亡的作用,且呈时间和剂量依赖关系;处理72h后,胰腺癌细胞线粒体跨膜电位明显下降,Bax表达上调,Bcl-2表达下降。结论：雷公藤甲素能有效抑制胰腺癌细胞增殖,通过增强线粒体通透性诱导细胞凋亡。