title: Effect ofin vivoadministration of reprogramming factors in the mouse liver.
abstract: Cancer is initiated by the transformation of stem cells or progenitor cells via a dedifferentiation process that leads to cancer stem cells; however, the process involves the activation of growth-promoting oncogenes and the inactivation of growth-constraining tumor suppressor genes. The introduction of defined factors, such as those encoded byc-Myc,Sox2,Oct3/4andKlf4,in normal somatic cells results in their dedifferentiation into induced pluripotent stem (iPS) cells. We previously reported that these defined factors induced the development of induced multipotent cancer (iPC) cells from gastrointestinal cancer cells by reducing tumor aggressiveness. Previous studies indicated that although reprogramming may be facilitated byp53inhibition, gain-of-function oncogenic mutations inp53and oncogenic mutations inKras-stimulated tumorigenic activity, and their rolesin vivoare imperfectly understood. Hence, in the present study, the effect of direct injection of a Sendai virus (SeV) vector encoding four defined factorsin vivowas studied using various backgrounds of transgenic and knockout mice, and was compared with that of direct injection of microRNAs (miRNAs) diluted with cationic lipid. Thein vivoimaging data revealed transformation hot spots forp53deficiency or conditional activation of mutantKras, and the sizes were concordant with those in immuno-deficient NOD/SCID and uPA-NOG mice, as well as larger compared with those in the control mice. Overall, the present data onin vivoreprogramming indicated thatKrasactivation may facilitate the effect of cellular reprogramming in normal liver cells, and the effect ofKrasactivation is more apparent than that of tumor suppressorp53deficiency. The results also revealed that immunodeficiency may increase the effect of reprogramming, presumably by blocking the immunosurveillance of transformed cells. These findings provide a rationale for further studies to develop a therapeutic approach involving directin vivoreprogramming.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871;
authors.forename: Akira
authors.initials: A
authors.lastname: Tomokuni
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hoshino
authors.forename: Dyah Laksmi
authors.initials: DL
authors.lastname: Dewi
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kano
authors.forename: Norikatsu
authors.initials: N
authors.lastname: Miyoshi
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hinohara
authors.forename: Noemi
authors.initials: N
authors.lastname: Fusaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Marubashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
keywords: Kras; differentiation; liver; p53; reprogramming