Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway

Takaharu Yasui, Kenoki Ohuchida, Ming Zhao, Manabu Onimaru, Takuya Egami, Hayato Fujita, Takao Ohtsuka, Kazuhiro Mizumoto, Masao Tanaka

Research output: Contribution to journalArticle

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Abstract

Many preclinical studies have shown the potential of adenovirus-based cancer gene therapy. However, successful translation of these promising results into the clinic has not yet been achieved. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant desmoplastic stroma, and tumor-stromal cell interactions play a critical role in tumor progression. Therefore, we hypothesized that tumor-stroma interactions reduce the efficacy of adenoviral therapy. We investigated the effect of fibroblasts on adenovirus-based gene therapy using SUIT-2 and PANC-1 pancreatic cancer cells cultured with or without fibroblast-conditioned culture supernatant then infected with Ad-LacZ. After 48h, the cells were stained for β-galactosidase. The results showed that the number of β-galactosidase-positive cells was significantly reduced after culture with fibroblast-conditioned supernatant (P<0.05). Because the hepatocyte growth factor (HGF)/MET pathway plays an important role in tumor-stroma interactions we next investigated the involvement of this pathway in tumor-stroma interactions leading to the decreased efficacy of adenoviral therapy. SUIT-2 cells were cultured with or without SU11274 (a MET inhibitor) and/or fibroblast-conditioned culture supernatant, then infected with Ad-GFP. After 48h, GFP-positive cells were counted. The number of GFP-positive cells in cultures containing fibroblast-conditioned supernatant plus SU11274 was significantly greater than in cultures without SU11274. In conclusion, our results suggest that stromal cells in PDAC reduce the efficacy of adenoviral therapy through a mechanism involving the HGF/MET pathway. Control of such tumor-stroma interactions may lead to improvements in adenoviral gene therapy for PDAC.

Original languageEnglish
Pages (from-to)484-491
Number of pages8
JournalCancer Science
Volume102
Issue number2
DOIs
Publication statusPublished - Feb 1 2011

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Hepatocyte Growth Factor
Fibroblasts
Galactosidases
Genetic Therapy
Neoplasms
Adenocarcinoma
Stromal Cells
Adenoviridae
Cultured Cells
Therapeutics
Neoplasm Genes
Pancreatic Neoplasms
Cell Communication
Cell Culture Techniques
((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway. / Yasui, Takaharu; Ohuchida, Kenoki; Zhao, Ming; Onimaru, Manabu; Egami, Takuya; Fujita, Hayato; Ohtsuka, Takao; Mizumoto, Kazuhiro; Tanaka, Masao.

In: Cancer Science, Vol. 102, No. 2, 01.02.2011, p. 484-491.

Research output: Contribution to journalArticle

Yasui, Takaharu ; Ohuchida, Kenoki ; Zhao, Ming ; Onimaru, Manabu ; Egami, Takuya ; Fujita, Hayato ; Ohtsuka, Takao ; Mizumoto, Kazuhiro ; Tanaka, Masao. / Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway. In: Cancer Science. 2011 ; Vol. 102, No. 2. pp. 484-491.
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