TY - JOUR
T1 - Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor
AU - Eguchi, Daiki
AU - Ikenaga, Naoki
AU - Ohuchida, Kenoki
AU - Kozono, Shingo
AU - Cui, Lin
AU - Fujiwara, Kenji
AU - Fujino, Minoru
AU - Ohtsuka, Takao
AU - Mizumoto, Kazuhiro
AU - Tanaka, Masao
N1 - Funding Information:
This work was supported in part by the following: a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan ; and grants from the Japanese Society of Gastroenterology and the Pancreas Research Foundation of Japan .
PY - 2013/5/15
Y1 - 2013/5/15
N2 - 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% O2) and hypoxia (1% O2), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule - connective 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.
AB - 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% O2) and hypoxia (1% O2), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule - connective 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.
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U2 - 10.1016/j.jss.2012.06.051
DO - 10.1016/j.jss.2012.06.051
M3 - Article
C2 - 22795353
AN - SCOPUS:84876408848
SN - 0022-4804
VL - 181
SP - 225
EP - 233
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 2
ER -
