Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer

Abstract

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. 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. IntroductionThe most frequent form of distant metastasis and recurrence in advanced gastric cancer (GC) is peritoneal metastasis, which is considered an independent predictor of poor prognosis and lacks curative treatment options.1Chau I. Norman A.R. Cunningham D. Waters J.S. Oates J. Ross P.J. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer–pooled analysis from three multicenter, randomized, controlled trials using individual patient data.J. Clin. Oncol. 2004; 22: 2395-2403https://doi.org/10.1200/jco.2004.08.154Google Scholar Although peritoneal metastasis is caused by dissemination of cancer cells from the primary site into the peritoneal cavity and implantation onto mesothelial cells, the tumor microenvironment, including extracellular matrix, cancer-associated fibroblasts (CAFs), and immune cells and their interactions, enhance cancer progression, metastasis, and the form of peritoneal metastasis.2Kalluri R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598https://doi.org/10.1038/nrc.2016.73Google Scholar, 3Quail D.F. Joyce J.A. Microenvironmental regulation of tumor progression and metastasis.Nat. Med. 2013; 19: 1423-1437https://doi.org/10.1038/nm.3394Google Scholar, 4Yasuda T. Koiwa M. Yonemura A. Miyake K. Kariya R. Kubota S. Yokomizo-Nakano T. Yasuda-Yoshihara N. Uchihara T. Itoyama R. et al.Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.Cell Rep. 2021; 34: 108779https://doi.org/10.1016/j.celrep.2021.108779Google Scholar CAFs are one of the important components of the tumor mesenchyme and are known to enhance cancer progression and metastasis.2Kalluri R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598https://doi.org/10.1038/nrc.2016.73Google Scholar,5Öhlund D. Elyada E. Tuveson D. Fibroblast heterogeneity in the cancer wound.J Exp Med. 2014; 211: 1503-1523Google Scholar CAFs differ from normal fibroblasts (NFs) in various structural and functional aspects. The expression and function of p53 are downmodulated in CAFs, and transcriptional alteration of p53 converts NFs to CAFs, which become cancer-supporting rather than cancer-inhibiting.6Procopio M.G. Laszlo C. Al Labban D. Kim D.E. Bordignon P. Jo S.H. Goruppi S. Menietti E. Ostano P. Ala U. et al.Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.Nat. Cell Biol. 2015; 17: 1193-1204https://doi.org/10.1038/ncb3228Google Scholar, 7Schmid J.O. Dong M. Haubeiss S. Friedel G. Bode S. Grabner A. Ott G. Murdter T.E. Oren M. Aulitzky W.E. van der Kuip H. Cancer cells cue the p53 response of cancer-associated fibroblasts to cisplatin.Cancer Res. 2012; 72: 5824-5832https://doi.org/10.1158/0008-5472.can-12-1201Google Scholar, 8Arandkar S. Furth N. Elisha Y. Nataraj N.B. van der Kuip H. Yarden Y. Aulitzky W. Ulitsky I. Geiger B. Oren M. Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features.Proc. Natl. Acad. Sci. U S A. 2018; 115: 6410-6415https://doi.org/10.1073/pnas.1719076115Google Scholar Mutation of the p53 gene is considered to occur in over 50% of all human cancers, because p53 plays tumor-suppressive roles and maintains genome integrity and cellular homeostasis by regulating cell-cycle arrest, senescence, apoptosis, and autophagy.9Bieging K.T. Mello S.S. Attardi L.D. Unravelling mechanisms of p53-mediated tumour suppression.Nat. Rev. Cancer. 2014; 14: 359-370https://doi.org/10.1038/nrc3711Google Scholar,10Muller P.A.J. Vousden K.H. p53 mutations in cancer.Nat. Cell Biol. 2013; 15: 2-8https://doi.org/10.1038/ncb2641Google Scholar therapy to the tumor p53 gene is a promising strategy to the of tumor B. J.A. gene Biol. Scholar trials using a in with various of cancers, and T. N. S. S. Y. T. K. T. Y. S. et study of of p53 in with advanced Clin. Oncol. Scholar, J. G. S.S. W. C. J. G. J. et p53 gene therapy efficacy in of the and Cancer Res. 15: Scholar, A. D. D. B. P. J.A. of an in with locally advanced a study of p53 gene Clin. Oncol. Scholar promising in the cancer a oncolytic which the and for of the human and in various human tumor T. S. N. Y. T. M. S. N. T. for human Cancer Res. 2004; Scholar, Y. Y. Y. S. H. K. N. H. Y. T. of biological and of Sci. Scholar, T. H. J. T. A. Y. S. R. S. et of oncolytic for human and Cancer Res. 17: Scholar intraperitoneal administration of synergistically the peritoneal metastasis of GC in with paclitaxel W. S. T. M. H. S. K. M. S. Y. T. and of oncolytic by paclitaxel peritoneal metastasis of gastric Scholar clinical was by with various J. M. N. C. N. S. et study of oncolytic for various Y. H. S. N. K. T. H. T. S. S. et study of of with in cancer for J. Cancer. 2021; Scholar OBP-702 a of the wild-type p53 OBP-702 the of various of tumor cells with p53 in tumor J. T. H. S. Y. T. A. Y. T. et by p53 resistance to oncolytic in human Cancer 2013; Scholar, T. H. T. H. T. R. S. S. R. Y. et of the in human 17: Scholar, T. H. T. H. M. T. Y. S. T. T. of cells by oncolytic Scholar The administration of is for peritoneal metastasis with therapy, because the peritoneal cavity in C. S. and of intraperitoneal cancer 2012; Scholar chemotherapy showed with chemotherapy in with peritoneal metastasis of M. S. J. of paclitaxel by paclitaxel and peritoneal in an study of the and Clin. Oncol. 19: Scholar, B. R. S. and paclitaxel in J. Med. Scholar, chemotherapy for with advanced Oncol. Scholar chemotherapy showed the of with chemotherapy in a for with peritoneal metastasis of H. Y. R. A. H. M. H. Y. Y. K. et intraperitoneal and paclitaxel in with gastric cancer with peritoneal Clin. Oncol. 2018; we found transcriptional alteration of p53 in CAFs to the of CAFs in peritoneal metastasis of administration of OBP-702 showed against peritoneal metastasis by modulating CAFs in addition to tumor p53 CAF expression is a poor prognostic factor and is for peritoneal the clinical of CAFs in GC, we with prognosis in of CAFs in primary tumor cells using The was an was in three for and the was gastric investigated to the of expression in the The of gastric was the CAFs and the prognosis of with with expression showed than with expression CAFs in the tumor microenvironment are to prognosis of the tumor microenvironment in peritoneal metastasis of GC, we immunohistochemical analysis of peritoneal from GC all and known CAF and in the fibroblasts cancer cells CAF expression in peritoneal metastasis was to the analysis of the primary peritoneal was investigated the of The of peritoneal was which was higher CAF expression was in all with peritoneal metastasis CAFs are to tumor progression, metastasis, and the form of peritoneal alteration of p53 we and CAFs from the of the GC and and and and in fibroblasts by and analysis to not an but the which is in CAFs and CAF and in the CAFs of was increased in and with we and CAFs and and secretion and CAFs. secretion was increased in CAFs by from also showed we investigated the of p53 in CAFs and using analysis in The cellular of p53 are to controlled by the of p53 was decreased in CAFs with and The decreased p53 was associated with This transcriptional alteration of p53 in CAFs to their of p53 in CAFs analysis of and CAFs from clinical the and analysis of and CAFs from clinical with a of and CAF and p53 in and CAFs. was a secretion in and CAFs. are was The of secretion of and CAFs. The of secretion the of of and CAFs. from and CAFs by and by analysis with p53 was a The relative of in the was and of OBP-702 and human gastric cancer is a oncolytic in which wild-type p53 gene was into the in the of OBP-702 and cells are to with OBP-702 Cell was in both and cells in a treatment with OBP-702 OBP-702 infection apoptosis by the of and autophagy by in human GC cells The therapy using OBP-702 and cancer in a of the a of therapy in both of human GC cells the of which the OBP-702, for p53 in of human tumor T. S. H. of oncolytic and for human 2012; T. S. H. Y. M. Y. R. Y. N. T. efficacy of oncolytic with of J. Cancer. Scholar showed the of in cancer cells, and therapy increased the of cancer cells, in W. S. T. M. H. S. K. M. S. Y. T. and of oncolytic by paclitaxel peritoneal metastasis of gastric Scholar the of OBP-702 and a human GC of OBP-702 and human gastric cancer and cells with OBP-702 the for with the for Cell was using the The of a was considered and relative are of and in cells with OBP-702 the was a The was with and of and a wild-type cytotoxicity to in a CAFs to in an The and OBP-702 oncolytic human cancer cells human and OBP-702 not the of which are normal not cytotoxicity to CAFs, OBP-702 was to CAFs in a in an and by showed which and OBP-702 infection of infection the of CAFs was also decreased with in the expression was and CAFs in a OBP-702 infection to CAFs by the of in a and OBP-702 infection the of in the of apoptosis and autophagy in CAFs the of CAFs caused by OBP-702, secretion of from CAFs was was not observed in infection of cancer-promoting cytokines, and from CAFs, decreased by OBP-702 cytokines increased in CAFs with OBP-702 CAFs by the of wild-type the function and of CAFs by and CAFs with OBP-702 the for with the for Cell was using the The of a was considered and relative are of and CAF with OBP-702 for by of the infection with of and in CAFs with OBP-702 the was a of from OBP-702 infection by are in cytokines from CAFs infection with of from the of cytokines by The of cytokines from was considered relative of cytokines from CAF with for peritoneal we administration of OBP-702 with peritoneal metastasis using a OBP-702 was tumor was OBP-702 for one The of OBP-702 and tumor growth with with OBP-702 and This using OBP-702 with a peritoneal metastases from metastasis of GC was by administration of OBP-702 in with in the The of with OBP-702 of with peritoneal metastasis with OBP-702, OBP-702 and in tumor was using the and tumor are was the of therapy using OBP-702 and peritoneal metastasis by both cancer cells and CAFs to tumor growth in the peritoneal we cancer cells cancer cells and CAF into the peritoneal cavity of and the tumor growth of CAFs tumor growth in the peritoneal cavity we the of therapy with OBP-702 and for a peritoneal metastasis with OBP-702 was and was also OBP-702 administration Combination therapy tumor in the peritoneal cavity treatment not tumor immunohistochemical therapy decreased the fibroblasts in peritoneal with and therapy using OBP-702 and therapeutic for the peritoneal metastasis of GC by the of both cancer cells and growth was by administration of OBP-702 in with of both cancer cells and CAFs in metastatic with CAFs into the cavity of in tumor was using the and tumor are of and CAFs with OBP-702 three tumor in the cavity and was are was analysis for expression of peritoneal The in the peritoneal using an by are was the tumor microenvironment of peritoneal metastasis, CAFs are fibroblasts cancer cells important roles in cancer cells and tumor growth cells, CAFs, in addition to cancer cells is important to peritoneal metastasis. This study CAFs by the transcriptional alteration of p53 in CAFs. we showed the therapeutic of administration of OBP-702 in with for peritoneal metastasis of GC by modulating CAFs in addition to tumor peritoneal metastasis is the and most frequent of metastasis and recurrence in advanced GC, the mechanisms peritoneal metastasis The and become the of peritoneal S. The of in cancer of the Rev. M. S. T. M. in the by gastric cancer cells for peritoneal Scholar cancer cells are with and the in the peritoneal site to The in the are CAFs and M. S. T. M. in the by gastric cancer cells for peritoneal S. S. K. A. H. Y. M. T. R. S. et microenvironment promotes peritoneal dissemination of gastric Scholar important roles in the and progression of peritoneal metastasis of GC CAFs also the of in to van der A. A. S. R. M. C. et and therapy resistance in Natl. Acad. Sci. U S A. E. M. D. S. et tumor cells and fibroblasts in the tumor Res. 2018; Scholar immunohistochemical of peritoneal of GC we both CAFs and in all CAFs are to peritoneal metastasis CAFs by cytokines by cancer cells also cytokines, T. Koiwa M. Yonemura A. Miyake K. Kariya R. Kubota S. Yokomizo-Nakano T. Yasuda-Yoshihara N. Uchihara T. Itoyama R. et al.Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.Cell Rep. 2021; 34: 108779https://doi.org/10.1016/j.celrep.2021.108779Google T. K. T. H. Y. H. S. R. T. H. et fibroblasts and cells in the tumor Cancer Res. 2018; Scholar in the to an important in tumor progression and of the D.E. the in cancer.Nat. Rev. Clin. Oncol. 2018; 15: H. D. H. a strategy to resistance to chemotherapy in gastric Cancer. Scholar CAFs from clinical showed higher expression and secretion with NFs to tumor progression and p53 plays a tumor-suppressive in fibroblasts by the and secretion of Y. N. D. G. Y. M. Oren M. p53 in fibroblasts tumor growth in an Res. N. A. J. T. Oren M. p53 cancer and of expression in Res. Scholar with cancer cells converts fibroblasts into R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598https://doi.org/10.1038/nrc.2016.73Google Scholar The of CAFs to M.G. Laszlo C. Al Labban D. Kim D.E. Bordignon P. Jo S.H. Goruppi S. Menietti E. Ostano P. Ala U. et al.Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.Nat. Cell Biol. 2015; 17: 1193-1204https://doi.org/10.1038/ncb3228Google Scholar, 7Schmid J.O. Dong M. Haubeiss S. Friedel G. Bode S. Grabner A. Ott G. Murdter T.E. Oren M. Aulitzky W.E. van der Kuip H. Cancer cells cue the p53 response of cancer-associated fibroblasts to cisplatin.Cancer Res. 2012; 72: 5824-5832https://doi.org/10.1158/0008-5472.can-12-1201Google Scholar, 8Arandkar S. Furth N. Elisha Y. Nataraj N.B. van der Kuip H. Yarden Y. Aulitzky W. Ulitsky I. Geiger B. Oren M. Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features.Proc. Natl. Acad. Sci. U S A. 2018; 115: 6410-6415https://doi.org/10.1073/pnas.1719076115Google Scholar Although CAFs are to not p53 p53 is in S. Furth N. Elisha Y. Nataraj N.B. van der Kuip H. Yarden Y. Aulitzky W. Ulitsky I. Geiger B. Oren M. Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features.Proc. Natl. Acad. Sci. U S A. 2018; 115: 6410-6415https://doi.org/10.1073/pnas.1719076115Google J. R. N. H. N. N. D. M. M. A. et cells p53 in Scholar CAFs in of p53 This alteration of p53 in CAFs to transcriptional of the normal tumor-suppressive of p53 into in CAFs. p53 is one of the most frequent for in the various P.A.J. Vousden K.H. p53 mutations in cancer.Nat. Cell Biol. 2013; 15: 2-8https://doi.org/10.1038/ncb2641Google Scholar p53 by gene an treatment strategy not cancer cells but also CAFs in oncolytic OBP-702, the wild-type p53 gene and apoptosis and autophagy in various of cancer J. T. H. S. Y. T. A. Y. T. et by p53 resistance to oncolytic in human Cancer 2013; T. H. T. H. T. R. S. S. R. Y. et of the in human 17: Scholar p53 is a of autophagy apoptosis, OBP-702 also apoptosis and autophagy in CAFs the of wild-type p53 Although of the oncolytic we is by the expression of in CAF was to in not the of CAFs in and not peritoneal metastasis in of wild-type p53 by OBP-702 to apoptosis and autophagy in we found oncolytic the of in human cancer S. The of in cancer of the Rev. M. M. S. M. N. T. Y. T. Y. M. administration of oncolytic cancer cells to and in a with peritoneal 17: Scholar, D. T. M. S. Y. Y. H. Y. T. of of oncolytic and for human Cancer Scholar, S. H. J. Y. T. K. T. T. T. T. et of expression by in human Rep. 2016; Scholar is for with oncolytic because in cells is not we the of and oncolytic in GC cells, because the efficacy of oncolytic and therapy increased the of a of caused by in cancer W. S. T. M. H. S. K. M. S. Y. T. and of oncolytic by paclitaxel peritoneal metastasis of gastric Scholar is also a for peritoneal metastasis, in the peritoneal cavity for a to using administration of the of in GC with peritoneal H. Y. R. A. H. M. H. Y. Y. K. et intraperitoneal and paclitaxel in with gastric cancer with peritoneal Clin. Oncol. 2018; Scholar therapy using administration of and OBP-702 the tumor growth of peritoneal clinical of of was in with a of advanced in the and the and of J. M. N. C. N. S. et study of oncolytic for various Scholar with was and showed clinical in with cancer for Y. H. S. N. K. T. H. T. S. S. et study of of with in cancer for J. Cancer. 2021; Scholar trials of administration of oncolytic for with cancer and the also E. J.S. P.J. I. P.J. et of intraperitoneal administration of an oncolytic to for Res. E. P.J. P. A. I. et the to Res. 2015; Scholar a we oncolytic is to metastatic in a W. S. T. M. H. S. K. M. S. Y. T. and of oncolytic by paclitaxel peritoneal metastasis of gastric Scholar administration of OBP-702 with the of CAFs in addition to tumor growth in the peritoneal The of OBP-702 and an treatment strategy for peritoneal metastasis of GC, because therapy not cancer cells but also CAFs to cancer we transcriptional alteration of p53 in CAFs OBP-702 not cancer cells but also CAFs by wild-type administration of OBP-702 and showed against peritoneal metastasis in an by both cancer cells and CAFs. oncolytic adenovirus-mediated p53 gene therapy in with offers a biological therapeutic strategy for peritoneal metastasis from and and in clinical of with GC and investigated and with peritoneal metastasis of GC of peritoneal and the of tumor was using with for CAFs cells and was using an in by including cells to CAFs. The from was the by an independent to clinical with a and with observed study the human GC and which with the cells from the of Cell and in with human from human K. M. Y. N. W. H. M. The of fibroblasts in Scholar CAFs from the gastric of the tumor and normal gastric fibroblasts from gastric CAFs and with and was from to the with and in a with and and T. S. N. Y. T. M. S. N. T. for human Cancer Res. 2004; Scholar, Y. Y. Y. S. H. K. N. H. Y. T. of biological and of Sci. Scholar, T. H. J. T. A. Y. S. R. S. et of oncolytic for human and Cancer Res. 17: Scholar OBP-702 is an a human wild-type p53 gene expression of the into the in a and wild-type also by using by a using cells, and the was was from and in human growth factor was from cells a of and for infection administration of Cell was using a Cell which is a to the from the The was with of the was the of and and of and in Rev. a of for three with cells in for cells with and three with cells with for with for with and for and with primary for the cells with for in by and using was from cells using the to the from the The was from of using was for gene expression analysis using the with The and was a The relative expression of was using the and CAFs in a a of and with for in the of to normal cells with OBP-702 for infection using a biological with was using an by cells in a a of with OBP-702 the for in and a and by and to with for and with the and using the of p53 in and CAFs, in the and and to the from the and primary of a of and with OBP-702 and using to the from the using was using a of and with OBP-702 in using a to the from the cells into the peritoneal cavity of of peritoneal of OBP-702 was and was also OBP-702 for tumor progression, the was a of in the with the in and from the cavity using the both and CAFs into OBP-702 was and and was also and tumor in the peritoneal cavity and was for immunohistochemical of peritoneal tumor with a and with the of was using the of the was using the with the for was to are of considered analysis was using study was in with the of the of and the for and human using clinical and by the of and by the for of IntroductionThe most frequent form of distant metastasis and recurrence in advanced gastric cancer (GC) is peritoneal metastasis, which is considered an independent predictor of poor prognosis and lacks curative treatment options.1Chau I. Norman A.R. Cunningham D. Waters J.S. Oates J. Ross P.J. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer–pooled analysis from three multicenter, randomized, controlled trials using individual patient data.J. Clin. Oncol. 2004; 22: 2395-2403https://doi.org/10.1200/jco.2004.08.154Google Scholar Although peritoneal metastasis is caused by dissemination of cancer cells from the primary site into the peritoneal cavity and implantation onto mesothelial cells, the tumor microenvironment, including extracellular matrix, cancer-associated fibroblasts (CAFs), and immune cells and their interactions, enhance cancer progression, metastasis, and the form of peritoneal metastasis.2Kalluri R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598https://doi.org/10.1038/nrc.2016.73Google Scholar, 3Quail D.F. Joyce J.A. Microenvironmental regulation of tumor progression and metastasis.Nat. Med. 2013; 19: 1423-1437https://doi.org/10.1038/nm.3394Google Scholar, 4Yasuda T. Koiwa M. Yonemura A. Miyake K. Kariya R. Kubota S. Yokomizo-Nakano T. Yasuda-Yoshihara N. Uchihara T. Itoyama R. et al.Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.Cell Rep. 2021; 34: 108779https://doi.org/10.1016/j.celrep.2021.108779Google Scholar CAFs are one of the important components of the tumor mesenchyme and are known to enhance cancer progression and metastasis.2Kalluri R. The biology and function of fibroblasts in cancer.Nat. Rev. Cancer. 2016; 16: 582-598https://doi.org/10.1038/nrc.2016.73Google Scholar,5Öhlund D. Elyada E. Tuveson D. Fibroblast heterogeneity in the cancer wound.J Exp Med. 2014; 211: 1503-1523Google Scholar CAFs differ from normal fibroblasts (NFs) in various structural and functional aspects. The expression and function of p53 are downmodulated in CAFs, and transcriptional alteration of p53 converts NFs to CAFs, which become cancer-supporting rather than cancer-inhibiting.6Procopio M.G. Laszlo C. Al Labban D. Kim D.E. Bordignon P. Jo S.H. Goruppi S. Menietti E. Ostano P. Ala U. et al.Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.Nat. Cell Biol. 2015; 17: 1193-1204https://doi.org/10.1038/ncb3228Google Scholar, 7Schmid J.O. Dong M. Haubeiss S. Friedel G. Bode S. Grabner A. Ott G. Murdter T.E. Oren M. Aulitzky W.E. van der Kuip H. Cancer cells cue the p53 response of cancer-associated fibroblasts to cisplatin.Cancer Res. 2012; 72: 5824-5832https://doi.org/10.1158/0008-5472.can-12-1201Google Scholar, 8Arandkar S. Furth N. Elisha Y. Nataraj N.B. van der Kuip H. Yarden Y. Aulitzky W. Ulitsky I. Geiger B. Oren M. Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features.Proc. Natl. Acad. Sci. U S A. 2018; 115: 6410-6415https://doi.org/10.1073/pnas.1719076115Google Scholar Mutation of the p53 gene is considered to occur in over 50% of all human cancers, because p53 plays tumor-suppressive roles and maintains genome integrity and cellular homeostasis by regulating cell-cycle arrest, senescence, apoptosis, and autophagy.9Bieging K.T. Mello S.S. Attardi L.D. Unravelling mechanisms of p53-mediated tumour suppression.Nat. Rev. Cancer. 2014; 14: 359-370https://doi.org/10.1038/nrc3711Google Scholar,10Muller P.A.J. Vousden K.H. p53 mutations in cancer.Nat. Cell Biol. 2013; 15: 2-8https://doi.org/10.1038/ncb2641Google Scholar therapy to the tumor p53 gene is a promising strategy to the of tumor B. J.A. gene Biol. Scholar trials using a in with various of cancers, and T. N. S. S. Y. T. K. T. Y. S. et study of of p53 in with advanced Clin. Oncol. Scholar, J. G. S.S. W. C. J. G. J. et p53 gene therapy efficacy in of the and Cancer Res. 15: Scholar, A. D. D. B. P. J.A. of an in with locally advanced a study of p53 gene Clin. Oncol. Scholar promising in the cancer a oncolytic which the and for of the human and in various human tumor T. S. N. Y. T. M. S. N. T. for human Cancer Res. 2004; Scholar, Y. Y. Y. S. H. K. N. H. Y. T. of biological and of Sci. Scholar, T. H. J. T. A. Y. S. R. S. et of oncolytic for human and Cancer Res. 17: Scholar intraperitoneal administration of synergistically the peritoneal metastasis of GC in with paclitaxel W. S. T. M. H. S. K. M. S. Y. T. and of oncolytic by paclitaxel peritoneal metastasis of gastric Scholar clinical was by with various J. M. N. C. N. S. et study of oncolytic for various Y. H. S. N. K. T. H. T. S. S. et study of of with in cancer for J. Cancer. 2021; Scholar OBP-702 a of the wild-type p53 OBP-702 the of various of tumor cells with p53 in tumor J. T. H. S. Y. T. A. Y. T. et by p53 resistance to oncolytic in human Cancer 2013; Scholar, T. H. T. H. T. R. S. S. R. Y. et of the in human 17: Scholar, T. H. T. H. M. T. Y. S. T. T. of cells by oncolytic Scholar The administration of is for peritoneal metastasis with therapy, because the peritoneal cavity in C. S. and of intraperitoneal cancer 2012; Scholar chemotherapy showed with chemotherapy in with peritoneal metastasis of M. S. J. of paclitaxel by paclitaxel and peritoneal in an study of the and Clin. Oncol. 19: Scholar, B. R. S. and paclitaxel in J. Med. Scholar, chemotherapy for with advanced Oncol. Scholar chemotherapy showed the of with chemotherapy in a for with peritoneal metastasis of H. Y. R. A. H. M. H. Y. Y. K. et intraperitoneal and paclitaxel in with gastric cancer with peritoneal Clin. Oncol. 2018; we found transcriptional alteration of p53 in CAFs to the of CAFs in peritoneal metastasis of administration of OBP-702 showed against peritoneal metastasis by modulating CAFs in addition to tumor p53

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