Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor

Daiki Eguchi, Naoki Ikenaga, Kenoki Ohuchida, Shingo Kozono, Lin Cui, Kenji Fujiwara, Minoru Fujino, Takao Ohtsuka, Kazuhiro Mizumoto, Masao Tanaka

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Abstract

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.

Original languageEnglish
Pages (from-to)225-233
Number of pages9
JournalJournal of Surgical Research
Volume181
Issue number2
DOIs
Publication statusPublished - May 15 2013

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Pancreatic Stellate Cells
Connective Tissue Growth Factor
Pancreatic Neoplasms
Neoplasms
Hypoxia

All Science Journal Classification (ASJC) codes

  • Surgery

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Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. / Eguchi, Daiki; Ikenaga, Naoki; Ohuchida, Kenoki; Kozono, Shingo; Cui, Lin; Fujiwara, Kenji; Fujino, Minoru; Ohtsuka, Takao; Mizumoto, Kazuhiro; Tanaka, Masao.

In: Journal of Surgical Research, Vol. 181, No. 2, 15.05.2013, p. 225-233.

Research output: Contribution to journalArticle

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abstract = "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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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

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