title: Retinoids in liver fibrosis and cancer.
abstract: Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-beta (TGF-beta), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-beta activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally. HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-alpha (RXRalpha) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of "clonal deletion" therapy for cancer chemoprevention, a new category of cancer chemotherapy.
authors.affiliation: First Department of the Internal Medicine, Gifu University School of Medicine, Gifu, Japan. mokuno@cc.gifu-u.ac.jp
authors.forename: Masataka
authors.initials: M
authors.lastname: Okuno
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Akita
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sano
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Takano
authors.forename: Koji
authors.initials: K
authors.lastname: Takai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Obora
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Yoshimune
authors.initials: Y
authors.lastname: Shiratori
authors.forename: Yukio
authors.initials: Y
authors.lastname: Okano
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Muto
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Moriwaki
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000517:prevention & control; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000517:prevention & control; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D012176:Retinoids / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D012176:Retinoids