TY - JOUR
T1 - Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer
AU - Ogawa, Toshihiro
AU - Kikuchi, Satoru
AU - Tabuchi, Motoyasu
AU - Mitsui, Ema
AU - Une, Yuta
AU - Tazawa, Hiroshi
AU - Kuroda, Shinji
AU - Noma, Kazuhiro
AU - Ohara, Toshiaki
AU - Kagawa, Shunsuke
AU - Urata, Yasuo
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
We thank Ms. Tomoko Sueishi, Ms. Tae Yamanishi, and Ms. Yuko Hoshijima for their excellent technical support. Yasuo Urata is the president and CEO of Oncolys BioPharma, the manufacturer of OBP-301 and OBP-702. Hiroshi Tazawa and Toshiyoshi Fujiwara are consultants for Oncolys BioPharma. The other authors have no real or potential conflicts of interest to declare. This work was supported by a grant-in-aid for early-career scientists from the Japan Society for the Promotion of Science (grant number 18K16362 ).
Funding Information:
We thank Ms. Tomoko Sueishi, Ms. Tae Yamanishi, and Ms. Yuko Hoshijima for their excellent technical support. Yasuo Urata is the president and CEO of Oncolys BioPharma, the manufacturer of OBP-301 and OBP-702. Hiroshi Tazawa and Toshiyoshi Fujiwara are consultants for Oncolys BioPharma. The other authors have no real or potential conflicts of interest to declare. This work was supported by a grant-in-aid for early-career scientists from the Japan Society for the Promotion of Science (grant number 18K16362). Conception and design: S. Kikuchi and T.F.; development of methodology: T. Ogawa, S. Kikuchi, and T.F.; acquisition of data: T. Ogawa, M.T. E.M. Y.U. and S. Kikuchi; analysis and interpretation of data: T. Ogawa, S. Kikuchi, H.T. K.N. and T.F.; writing, review, and/or revision of the manuscript: T. Ogawa and S. Kikuchi; administrative, technical, or material support: Y.U.; study supervision: S. Kikuchi, S. Kuroda, K.N. T. Ohara, and S. Kagawa, and T.F. Yasuo Urata is the president and CEO of Oncolys BioPharma, the manufacturer of OBP-702. Hiroshi Tazawa and Toshiyoshi Fujiwara are consultants for Oncolys BioPharma. The other authors have no real or potential conflicts of interest to declare.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/6/16
Y1 - 2022/6/16
N2 - 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.
AB - 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.
KW - adenovirus
KW - cancer-associated fibroblast
KW - gastric cancer
KW - oncolytic virus
KW - p53
KW - paclitaxel
KW - peritoneal metastasis
UR - http://www.scopus.com/inward/record.url?scp=85129554984&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129554984&partnerID=8YFLogxK
U2 - 10.1016/j.omto.2022.04.009
DO - 10.1016/j.omto.2022.04.009
M3 - Article
AN - SCOPUS:85129554984
SN - 2372-7705
VL - 25
SP - 249
EP - 261
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
ER -
