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Article

Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice

  • Authors:
    • Joong Sun Kim
    • Yeonghoon Son
    • Min Ji Bae
    • Minyoung Lee
    • Chang Geun Lee
    • Wol Soon Jo
    • Sung Dae Kim
    • Kwangmo Yang
  • View Affiliations / Copyright

    Affiliations: Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea
  • Pages: 147-154
    |
    Published online on: May 13, 2015
       https://doi.org/10.3892/or.2015.3977
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Abstract

Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.
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1 

Mauch P, Constine L, Greenberger J, Knospe W, Sullivan J, Liesveld JL and Deeg HJ: Hematopoietic stem cell compartment: Acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys. 31:1319–1339. 1995. View Article : Google Scholar : PubMed/NCBI

2 

Friberg LE, Henningsson A, Maas H, Nguyen L and Karlsson MO: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 20:4713–4721. 2002. View Article : Google Scholar : PubMed/NCBI

3 

Sung L and Dror Y: Clinical applications of granulocyte-colony stimulating factor. Front Biosci. 12:1988–2002. 2007. View Article : Google Scholar

4 

MacVittie TJ and Farese AM: Cytokine-based treatment of radiation injury: Potential benefits after low-level radiation exposure. Mil Med. 167(Suppl): 68–70. 2002.PubMed/NCBI

5 

Uckun FM, Souza L, Waddick KG, Wick M and Song CW: In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice. Blood. 75:638–645. 1990.PubMed/NCBI

6 

Hou XW, Jiang Y, Wang LF, Xu HY, Lin HM, He XY, He JJ and Zhang S: Protective role of granulocyte colony-stimulating factor against adriamycin induced cardiac, renal and hepatic toxicities. Toxicol Lett. 187:40–44. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Kim JS, Yang M, Jang H, Oui H, Kim SH, Shin T, Jang WS, Lee SS and Moon C: Granulocyte-colony stimulating factor ameliorates irradiation-induced suppression of hippocampal neurogenesis in adult mice. Neurosci Lett. 486:43–46. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Kudo T, Matsumoto T, Nakamichi I, Yada S, Esaki M, Jo Y, Ohji Y, Yao T and Iida M: Recombinant human granulocyte colony-stimulating factor reduces colonic epithelial cell apoptosis and ameliorates murine dextran sulfate sodium-induced colitis. Scand J Gastroenterol. 43:689–697. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Kim JS, Ryoo SB, Heo K, Kim JG, Son TG, Moon C and Yang K: Attenuating effects of granulocyte-colony stimulating factor (G-CSF) in radiation induced intestinal injury in mice. Food Chem Toxicol. 50:3174–3180. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Kim JS, Yang M, Lee CG, Kim SD, Kim JK and Yang K: In vitro and in vivo protective effects of granulocyte colony-stimulating factor against radiation-induced intestinal injury. Arch Pharm Res. 36:1252–1261. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Lopez-Lazaro M: Granulocyte colony-stimulating factor (G-CSF): A novel anticancer therapy based on the ‘universal dynamics of tumor growth’? Exp Oncol. 28:249–251. 2006.PubMed/NCBI

12 

Maeda H, Uozumi T, Kurisu K, Matsuoka T, Kawamoto K, Kiya K, Ogasawara H, Sugiyama K, Mikami T, Monden S, et al: Combined antitumor effects of TNF and G-CSF on a human medulloblastoma xenograft line. J Neurooncol. 21:203–213. 1994. View Article : Google Scholar : PubMed/NCBI

13 

Natori T, Sata M, Washida M, Hirata Y, Nagai R and Makuuchi M: G-CSF stimulates angiogenesis and promotes tumor growth: Potential contribution of bone marrow-derived endothelial progenitor cells. Biochem Biophys Res Commun. 297:1058–1061. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Voloshin T, Gingis-Velitski S, Bril R, Benayoun L, Munster M, Milsom C, Man S, Kerbel RS and Shaked Y: G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: Prevention by a CXCR4 antagonist. Blood. 118:3426–3435. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Roberts AW: G-CSF: A key regulator of neutrophil production, but that’s not all! Growth Factors. 23:33–41. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Hérodin F and Drouet M: Cytokine-based treatment of accidentally irradiated victims and new approaches. Exp Hematol. 33:1071–1080. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Singh VK, Fatanmi OO, Singh PK and Whitnall MH: Role of radiation-induced granulocyte colony-stimulating factor in recovery from whole body gamma-irradiation. Cytokine. 58:406–414. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z and Kolesnick R: Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 300:1155–1159. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Romero-Weaver AL, Wan XS, Diffenderfer ES, Lin L and Kennedy AR: Kinetics of neutrophils in mice exposed to radiation and/or granulocyte colony-stimulating factor treatment. Radiat Res. 180:177–188. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG and Ferrara N: G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA. 106:6742–6747. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Chen FH, Fu SY, Yang YC, Wang CC, Chiang CS and Hong JH: Combination of vessel-targeting agents and fractionated radiation therapy: The role of the SDF-1/CXCR4 pathway. Int J Radiat Oncol Biol Phys. 86:777–784. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Bottoni U, Bonaccorsi P, Devirgiliis V, Panasiti V, Borroni RG, Trasimeni G, Clerico R and Calvieri S: Complete remission of brain metastases in three patients with stage IV melanoma treated with BOLD and G-CSF. Jpn J Clin Oncol. 35:507–513. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten H, de Greef G, Ferrant A, et al: Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 349:743–752. 2003. View Article : Google Scholar : PubMed/NCBI

24 

Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A and Musiani P: The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 97:339–345. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Koga Y, Matsuzaki A, Suminoe A, Hattori H and Hara T: Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): A novel mechanism of antitumor effect by neutrophils. Cancer Res. 64:1037–1043. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Ohki Y, Heissig B, Sato Y, Akiyama H, Zhu Z, Hicklin DJ, Shimada K, Ogawa H, Daida H, Hattori K, et al: Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J. 19:2005–2007. 2005.PubMed/NCBI

28 

Roskoski R Jr: Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 62:179–213. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, et al: Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 109:625–637. 2002. View Article : Google Scholar : PubMed/NCBI

30 

Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, et al: Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 97:3354–3360. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR and Brown JM: Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 120:694–705. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Prionas SD, Kowalski J, Fajardo LF, Kaplan I, Kwan HH and Allison AC: Effects of X irradiation on angiogenesis. Radiat Res. 124:43–49. 1990. View Article : Google Scholar : PubMed/NCBI

33 

Heissig B, Hattori K, Friedrich M, Rafii S and Werb Z: Angiogenesis: Vascular remodeling of the extracellular matrix involves metalloproteinases. Curr Opin Hematol. 10:136–141. 2003. View Article : Google Scholar : PubMed/NCBI

34 

Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, et al: Matrix metallopro-teinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2:737–744. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Ahn GO and Brown JM: Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: Role of bone marrow-derived myelomonocytic cells. Cancer Cell. 13:193–205. 2008. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Kim JS, Son Y, Bae MJ, Lee M, Lee CG, Jo WS, Kim SD and Yang K: Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice. Oncol Rep 34: 147-154, 2015.
APA
Kim, J.S., Son, Y., Bae, M.J., Lee, M., Lee, C.G., Jo, W.S. ... Yang, K. (2015). Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice. Oncology Reports, 34, 147-154. https://doi.org/10.3892/or.2015.3977
MLA
Kim, J. S., Son, Y., Bae, M. J., Lee, M., Lee, C. G., Jo, W. S., Kim, S. D., Yang, K."Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice". Oncology Reports 34.1 (2015): 147-154.
Chicago
Kim, J. S., Son, Y., Bae, M. J., Lee, M., Lee, C. G., Jo, W. S., Kim, S. D., Yang, K."Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice". Oncology Reports 34, no. 1 (2015): 147-154. https://doi.org/10.3892/or.2015.3977
Copy and paste a formatted citation
x
Spandidos Publications style
Kim JS, Son Y, Bae MJ, Lee M, Lee CG, Jo WS, Kim SD and Yang K: Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice. Oncol Rep 34: 147-154, 2015.
APA
Kim, J.S., Son, Y., Bae, M.J., Lee, M., Lee, C.G., Jo, W.S. ... Yang, K. (2015). Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice. Oncology Reports, 34, 147-154. https://doi.org/10.3892/or.2015.3977
MLA
Kim, J. S., Son, Y., Bae, M. J., Lee, M., Lee, C. G., Jo, W. S., Kim, S. D., Yang, K."Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice". Oncology Reports 34.1 (2015): 147-154.
Chicago
Kim, J. S., Son, Y., Bae, M. J., Lee, M., Lee, C. G., Jo, W. S., Kim, S. D., Yang, K."Administration of granulocyte colony-stimulating factor with radiotherapy promotes tumor growth by stimulating vascularization in tumor-bearing mice". Oncology Reports 34, no. 1 (2015): 147-154. https://doi.org/10.3892/or.2015.3977
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