title: Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway.
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 48 h, 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 48 h, 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.
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Yasui
authors.forename: Kenoki
authors.initials: K
authors.lastname: Ohuchida
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Manabu
authors.initials: M
authors.lastname: Onimaru
authors.forename: Takuya
authors.initials: T
authors.lastname: Egami
authors.forename: Hayato
authors.initials: H
authors.lastname: Fujita
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000628:therapy; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; C066855:HGF protein, human; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met