Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal
metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene
therapy (OBP-702) against CAFs and peritoneal
metastasis of
gastric cancer (GC). Higher CAF expression in the primary
tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal
metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of
cancer-promoting
cytokines, including
interleukin-6, and gained resistance to
chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702
infection caused apoptosis and autophagy of CAFs and decreased the secretion of
cancer-promoting
cytokines by CAFs. Combination
therapy using intraperitoneal administration of OBP-702 and
paclitaxel synergistically inhibited the
tumor growth of peritoneal
metastases and decreased CAFs in peritoneal
metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene
therapy, offers a promising biological therapeutic strategy for peritoneal
metastasis, modulating CAFs in addition to achieving
tumor lysis.