Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells.
It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment.
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Hiroshi
H
Tazawa
Tokuichi
T
Kawaguchi
Tokushige
T
Kobayashi
Yasuhiro
Y
Kuramitsu
Sayori
S
Wada
Yoshiko
Y
Satomi
Hoyoku
H
Nishino
Masanobu
M
Kobayashi
Yusuke
Y
Kanda
Mitsuhiko
M
Osaki
Tomoyuki
T
Kitagawa
Masuo
M
Hosokawa
Futoshi
F
Okada
D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology; D000236:Adenoma / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; C004479:pimagedine
AG; Anoikis; Chronic inflammation; Colon carcinogenesis; FPCK-1-1; FPCK-1-1 cells serially exposed NaOH (vehicle); FPCK-1-1 cells serially exposed to NOC18 in 2-dimensional cell culture; FPCK/Inflam; FPCK/NO; FPCK/NO/3D; FPCK/NaOH; Human colonic adenoma cells; NO; Nitric oxide; Three-dimensional culture; a human colonic adenoma cells; aminoguanidine; colon adenocarcinoma cells derived from FPCK-1-1 cells by chronic inflammation in vivo; nitric oxide; survived cells of FPCK/NO cells after they were grown in 3D culture