title: Involvement of reactive nitrogen oxides for acquisition of metastatic properties of benign tumors in a model of inflammation-based tumor progression.
abstract: The cells of a weakly tumorigenic and non-metastatic murine fibrosarcoma (QR-32) are converted into highly malignant tumors (acquiring metastatic potential) once they have grown in vivo after being co-implanted with gelatin sponge which induces inflammation. In the present study, we examined whether nitric oxide (NO) is involved in the inflammation-based tumor progression by administrating a specific inhibitor to inducible nitric oxide synthase, aminoguanidine (AG). First, we co-implanted 1 x 10(5) QR-32 cells with gelatin sponge (10 x 5 x 3 mm piece) into a subcutaneous space in C57BL6 mice. Administration of AG in drinking water (1%) had started 2 days before the tumor implantation and continued until the termination of the experiment. The incidence of tumor formation and the tumor growth did not differ between AG-treated group and -untreated group. On day 28, we excised the arising tumors to establish culture cell lines for evaluation of their acquisition of metastatic phenotype in other normal mice. Metastasis incidence and the number of metastatic colonies were significantly reduced in the tumor cell lines obtained from AG-treated mice compared to those from non-treated mice (p < 0.05). Immunohistochemical analysis demonstrated that inducible nitric oxide synthase and nitrotyrosine in the inflamed lesion were reduced in the AG-administered mice. However, intensity of 8-hydroxy-2-deoxyguanosine was not different between the groups. These results showed that nitric oxide and its reactive nitrogen oxide species cooperatively play a pivotal role in the progression of benign tumor cells in inflamed lesions.
authors.affiliation: Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan. fuokada@med.id.yamagata-u.ac.jp
authors.forename: Futoshi
authors.initials: F
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.forename: Tokushige
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Masuo
authors.initials: M
authors.lastname: Hosokawa
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology*; D005781:Gelatin Sponge, Absorbable; D019791:Guanidine / Q000031:analogs & derivatives; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D007249:Inflammation / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D010084:Oxidation-Reduction; D026361:Reactive Nitrogen Species / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000502:physiology
chemical_list: D026361:Reactive Nitrogen Species; C033495:8-aminoguanine; C002744:3-nitrotyrosine; D014443:Tyrosine; D006147:Guanine; D052247:Nitric Oxide Synthase Type II; D019791:Guanidine