title: Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells.
abstract: BACKGROUND
  Although operative injury is thought generally to worsen the prognosis of cancer patients, the relevant mechanisms are not yet understood fully. We tested the hypothesis that operative injury induces mobilization and recruitment of bone marrow stem cells, thereby enhancing angiogenesis and accelerating tumor growth.
  
  
  METHODS
  Mice were subjected to an open gastrotomy, and naïve mice were used as controls. The mobilization of bone marrow stem cells was monitored after operation. Using an established tumor model in green fluorescent protein (GFP)(+) bone marrow-transplanted chimera mice, we investigated further whether the mobilized stem cells affected tumor growth.
  
  
  RESULTS
  Compared with the control, gastrotomy increased the populations of CD34(+) cells (6.9 ± 4.5 % vs 3.3 ± 0.4%, P < .05) and CD34(+)/Flk-1(+) cells (0.08 ± 0.02% vs 0.05 ± 0.01%, P < .05) in peripheral blood 12 h after operation. Twelve days after operation, the tumor volume almost doubled in mice after gastrotomy compared with control (580 ± 106 mm(3) vs 299 ± 162 mm(3), P < .05). A histologic analysis of tumor tissue revealed that the microvessel density and number of proliferating cells were significantly greater, but those of apoptotic cells were significantly less, in mice after gastrotomy as compared with control. Furthermore, the number of GFP(+) cells found in tumor tissue was significantly greater in mice that underwent gastrotomy than in controls. Some of the stained GFP(+) cells were positive for CD34 and had been incorporated into microvessels. Administration of AMD3100, which is an antagonist of stromal-cell-derived factor (SDF)-1/CXCR4 signaling pathway, inhibited the recruitment of GFP(+) cells and negated completely the acceleration in tumor growth after operation (345 ± 172 mm(3), P < .05).
  
  
  CONCLUSIONS
  Operative injury may induce the mobilization and recruitment of bone marrow stem cells, thereby enhancing angiogenesis and accelerating tumor growth. Inhibition of the SDF-1/CXCR4 signals may represent a new therapeutic strategy for preventing acceleration of tumor growth after operation.
authors.affiliation: Department of Surgery and Clinical Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takemoto
authors.forename: Tao-Sheng
authors.initials: TS
authors.lastname: Li
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kubo
authors.forename: Mako
authors.initials: M
authors.lastname: Ohshima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ueda
authors.forename: Eijirou
authors.initials: E
authors.lastname: Harada
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Enoki
authors.forename: Mariko
authors.initials: M
authors.lastname: Okamoto
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Murata
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000601:surgery*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins