title: Inhibition of HGF/cMET expression prevents distant recurrence of rectal             cancer after preoperative chemoradiotherapy.
abstract: Hepatocyte growth factor (HGF) and its receptor cMET play an important role             in tumor proliferation, invasion and metastasis. In this study, we investigated             the association of HGF/cMET signaling with distant recurrence in rectal cancer             after preoperative chemoradiotherapy and whether inhibition of the HGF/cMET signaling             pathway could suppress the re-growth of cancer cells after irradiation. We obtained             total RNA from residual cancer cells and stromal tissue separately using microdissection             from a total of 53 rectal cancer specimens from patients who underwent preoperative             CRT, performed transcriptional analyses, and analyzed the association of HGF and             cMET expression levels with clinical outcomes. We performed in vitro experiments             to examine HGF and cMET expression and the re-growth of cancer cells after irradiation             and treatment with a tyrosine kinase inhibitor specific for cMET (SU11274). We             found significant correlations between cancer cell HGF and cMET gene expression,             and stromal cell HGF and cancer cell cMET expression. Elevated cancer cell cMET             and stromal HGF expression were significantly associated with a worse prognosis.             In vitro experiments showed that the up-regulation of HGF expression and the re-growth             of irradiated cancer cells were effectively suppressed by inhibiting cMET. Our             results suggest that inhibition of radiation-induced HGF up-regulation and blockade             of autocrine/paracrine HGF/cMET signaling are potential new strategies for controlling             distant recurrence in rectal cancer patients after preoperative CRT.
authors.affiliation: Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. saigusa@clin.medic.mie-u.ac.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Saigusa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Toiyama
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujikawa
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsushita
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Okugawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.forename: Keiichi
authors.initials: K
authors.lastname: Uchida
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Mohri
authors.forename: Masato
authors.initials: M
authors.lastname: Kusunoki
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000517:prevention & control / Q000556:secondary / Q000628:therapy*; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059186:Chemoradiotherapy, Adjuvant; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D010879:Piperazines / Q000494:pharmacology; D011300:Preoperative Care; D011379:Prognosis; D012372:ROC Curve; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012004:Rectal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D000906:Antibodies; C066855:HGF protein, human; D007211:Indoles; D010879:Piperazines; D013449:Sulfonamides; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases