Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor
Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor
复制标题
DOI：
10.1016/j.jss.2012.06.051
复制
发表时间：
2013-05-15
影响因子：
2.2
通讯作者：
Tanaka, Masao
中科院分区：
文献类型：
--
作者：
Eguchi, Daiki;Ikenaga, Naoki;Tanaka, Masao
背景：胰腺癌（PC）是一种低血管肿瘤，在缺氧条件下生长。胰腺星状细胞（PSCs）通过分泌可溶性因子促进PC的进展，但其在缺氧条件下的功能尚不清楚。本研究旨在阐明缺氧条件对PC细胞和psc相互作用的影响。方法：我们从新鲜胰腺导管腺癌中分离人PSCs，分析常氧（21% O-2）和低氧（1% O-2）下PSCs的功能差异，包括与肿瘤间质相互作用相关的各种因子的表达。我们使用RNA干扰技术，特别分析了缺氧条件下PSCs中过表达的结缔组织生长因子（CTGF）对PC侵袭性的影响。结果：低氧PSCs培养的条件培养基对PC细胞侵袭性的增强作用强于常氧PSCs培养的条件培养基（P < 0.01）。与PSCs共培养时，低氧条件下PC细胞的侵袭能力强于常氧条件（P < 0.05）。在多种与侵袭性相关的可溶性因子中，CTGF是缺氧psc中过表达的分子之一。低氧PSCs上清液中CTGF的表达水平也高于常氧PSCs上清液。低氧PSCs与PC细胞共培养后，CTGF下调可降低PC细胞的侵袭性（P < 0.05）。结论：缺氧诱导PSCs分泌CTGF，导致PC侵袭性增强。缺氧刺激的PSCs衍生的CTGF可能成为胰腺癌新的治疗靶点。(C) 2013爱思唯尔公司版权所有。
Background: Pancreatic cancer (PC), a hypovascular tumor, thrives under hypoxic conditions. Pancreatic stellate cells (PSCs) promote PC progression by secreting soluble factors, but their functions in hypoxia are poorly understood. This study aimed to clarify the effects of hypoxic conditions on the interaction between PC cells and PSCs.Methods: We isolated human PSCs from fresh pancreatic ductal adenocarcinomas and analyzed functional differences in PSCs between normoxia (21% O-2) and hypoxia (1% O-2), including expression of various factors related to tumorestromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed moleculedconnective tissue growth factor (CTGF)-in PSCs under hypoxic conditions, using RNA interference techniques.Results: Conditioned media from hypoxic PSCs enhanced PC cell invasiveness more intensely than that from normoxic PSCs (P < 0.01). When co-cultured with PSCs, PC cell invasion was more enhanced under hypoxia than under normoxia (P < 0.05). Among various soluble factors, which were related to invasiveness, CTGF was one of the overexpressed molecules in hypoxic PSCs. A higher level of CTGF expression was also found in supernatant of hypoxic PSCs than in supernatant of normoxic PSCs. PC cell invasiveness was reduced by CTGF knockdown in hypoxic PSCs co-cultured with PC cells (P < 0.05).Conclusion: Hypoxia induces PSCs' secretion of CTGF, leading to enhancement of PC invasiveness. CTGF derived from hypoxia-stimulated PSCs may be a new therapeutic target for pancreatic cancer. (C) 2013 Elsevier Inc. All rights reserved.