Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells

Yoshihiro Takemoto, Tao Sheng Li, Masayuki Kubo, Mako Ohshima, Kazuhiro Ueda, Eijirou Harada, Tadahiko Enoki, Mariko Okamoto, Yoichi Mizukami, Tomoaki Murata, Kimikazu Hamano

Research output: Contribution to journalArticle

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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 mm3 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 mm3, P <.05). Conclusion: 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.

Original languageEnglish
Pages (from-to)792-800
Number of pages9
JournalSurgery
Volume149
Issue number6
DOIs
Publication statusPublished - Jun 2011
Externally publishedYes

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Stem Cells
Bone Marrow
Wounds and Injuries
Growth
Green Fluorescent Proteins
Neoplasms
Bone Marrow Cells
Chemokine CXCL12
Microvessels
Neoplastic Stem Cells
Tumor Burden
Cell Count
Population

ASJC Scopus subject areas

  • Surgery

Cite this

Takemoto, Y., Li, T. S., Kubo, M., Ohshima, M., Ueda, K., Harada, E., ... Hamano, K. (2011). Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells. Surgery, 149(6), 792-800. https://doi.org/10.1016/j.surg.2011.02.005

Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells. / Takemoto, Yoshihiro; Li, Tao Sheng; Kubo, Masayuki; Ohshima, Mako; Ueda, Kazuhiro; Harada, Eijirou; Enoki, Tadahiko; Okamoto, Mariko; Mizukami, Yoichi; Murata, Tomoaki; Hamano, Kimikazu.

In: Surgery, Vol. 149, No. 6, 06.2011, p. 792-800.

Research output: Contribution to journalArticle

Takemoto, Y, Li, TS, Kubo, M, Ohshima, M, Ueda, K, Harada, E, Enoki, T, Okamoto, M, Mizukami, Y, Murata, T & Hamano, K 2011, 'Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells', Surgery, vol. 149, no. 6, pp. 792-800. https://doi.org/10.1016/j.surg.2011.02.005
Takemoto, Yoshihiro ; Li, Tao Sheng ; Kubo, Masayuki ; Ohshima, Mako ; Ueda, Kazuhiro ; Harada, Eijirou ; Enoki, Tadahiko ; Okamoto, Mariko ; Mizukami, Yoichi ; Murata, Tomoaki ; Hamano, Kimikazu. / Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells. In: Surgery. 2011 ; Vol. 149, No. 6. pp. 792-800.
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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 na{\"i}ve 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 mm3 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 mm3, P <.05). Conclusion: 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.",
author = "Yoshihiro Takemoto and Li, {Tao Sheng} and Masayuki Kubo and Mako Ohshima and Kazuhiro Ueda and Eijirou Harada and Tadahiko Enoki and Mariko Okamoto and Yoichi Mizukami and Tomoaki Murata and Kimikazu Hamano",
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T1 - Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells

AU - Takemoto, Yoshihiro

AU - Li, Tao Sheng

AU - Kubo, Masayuki

AU - Ohshima, Mako

AU - Ueda, Kazuhiro

AU - Harada, Eijirou

AU - Enoki, Tadahiko

AU - Okamoto, Mariko

AU - Mizukami, Yoichi

AU - Murata, Tomoaki

AU - Hamano, Kimikazu

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N2 - 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 mm3 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 mm3, P <.05). Conclusion: 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.

AB - 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 mm3 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 mm3, P <.05). Conclusion: 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.

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