Pediatric Surgery International

, Volume 35, Issue 12, pp 1403–1411 | Cite as

Enhanced metastatic growth after local tumor resection in the presence of synchronous metastasis in a mouse allograft model of neuroblastoma

  • Maho InoueEmail author
  • Yoshiki Tsuchiya
  • Nobuya Koike
  • Yasuhiro Umemura
  • Hitoshi Inokawa
  • Yuichi Togashi
  • Junnosuke Maniwa
  • Mayumi Higashi
  • Shigehisa Fumino
  • Tatsuro Tajiri
  • Kazuhiro Yagita
Original Article



We investigated how local tumor resection affects metastatic lesions in neuroblastoma.


MYCN Tg tumor-derived cells were injected subcutaneously into 129+Ter/SvJcl wild-type mice. First, the frequency of metastasis-bearing mice was investigated immunohistochemically (metastatic ratio) at endpoint or post-injection day (PID) 90. Second, the threshold volume of local tumor in mice bearing microscopic lymph node metastasis (mLNM) was investigated at PID 30. Finally, local tumors were resected after exceeding the threshold. Mice were divided into local tumor resection (Resection) and observation (Observation) groups, and the metastatic ratio and volume of LNM were compared between the groups at endpoint or PID 74.


The metastatic ratio without local resection was 88% at PID 78–90. The threshold local tumor volume in the mice with mLNM was 745 mm3 at PID 30, so local tumors were resected after exceeding 700 mm3. The metastatic ratio and LNM volume were significantly greater in the Resection group (n = 16) than in the Observation group (n = 16) (94% vs. 38%, p < 0.001; 2092 ± 2310 vs. 275 ± 218 mm3, p < 0.01; respectively) at PID 50–74.


Local tumor resection might augment the growth of synchronous microscopic metastases. Our results provide insights into the appropriate timing of local resection for high-risk neuroblastoma.


Neuroblastoma Metastasis Local tumor resection Concomitant tumor resistance MYCN transgenic mouse 



This work was supported in part by Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT KAKENHI grant number 18H02600 [KY], 16K19008 [YU] and 15H05000 [TT]). The English used in this manuscript was reviewed by Brian Quinn (Editor-in-Chief, Japan Medical Communication).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest in association with the present study.


  1. 1.
    Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM, Children’s Oncology G (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363(14):1324–1334. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, LaQuaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG (2013) Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14(10):999–1008. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hishiki T, Matsumoto K, Ohira M, Kamijo T, Shichino H, Kuroda T, Yoneda A, Soejima T, Nakazawa A, Takimoto T, Yokota I, Teramukai S, Takahashi H, Fukushima T, Kaneko T, Hara J, Kaneko M, Ikeda H, Tajiri T, Nakagawara A, Japan Childhood Cancer Group Neuroblastoma C (2018) Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG). Int J Clin Oncol 23(5):965–973. CrossRefGoogle Scholar
  4. 4.
    Tohme S, Simmons RL, Tsung A (2017) Surgery for Cancer: a Trigger for Metastases. Cancer Res 77(7):1548–1552. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Alieva M, van Rheenen J, Broekman MLD (2018) Potential impact of invasive surgical procedures on primary tumor growth and metastasis. Clin Exp Metastasis 35(4):319–331. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Moon SB, Park KW, Jung SE, Youn WJ (2009) Neuroblastoma: treatment outcome after incomplete resection of primary tumors. Pediatr Surg Int 25(9):789–793. CrossRefPubMedGoogle Scholar
  7. 7.
    Adkins ES, Sawin R, Gerbing RB, London WB, Matthay KK, Haase GM (2004) Efficacy of complete resection for high-risk neuroblastoma: a Children’s Cancer Group study. J Pediatr Surg 39(6):931–936. CrossRefPubMedGoogle Scholar
  8. 8.
    La Quaglia MP, Kushner BH, Su W, Heller G, Kramer K, Abramson S, Rosen N, Wolden S, Cheung NK (2004) The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39(3):412–417. CrossRefPubMedGoogle Scholar
  9. 9.
    Du L, Liu L, Zhang C, Cai W, Wu Y, Wang J, Lv F (2014) Role of surgery in the treatment of patients with high-risk neuroblastoma who have a poor response to induction chemotherapy. J Pediatr Surg 49(4):528–533. CrossRefPubMedGoogle Scholar
  10. 10.
    Weiss WA, Mohapatra G, Feuerstein BG, Bishop JM (1997) Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J 16(11):2985–2995. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rasmuson A, Segerstrom L, Nethander M, Finnman J, Elfman LH, Javanmardi N, Nilsson S, Johnsen JI, Martinsson T, Kogner P (2012) Tumor development, growth characteristics and spectrum of genetic aberrations in the TH-MYCN mouse model of neuroblastoma. PLoS One 7(12):e51297. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Suenaga Y, Islam SM, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibata T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A (2014) NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3beta resulting in the stabilization of MYCN in human neuroblastomas. PLoS Genet 10(1):e1003996. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cao D, Kishida S, Huang P, Mu P, Tsubota S, Mizuno M, Kadomatsu K (2014) A new tumorsphere culture condition restores potentials of self-renewal and metastasis of primary neuroblastoma in a mouse neuroblastoma model. PLoS One 9(1):e86813. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K (2017) PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma. Cancer Res 77(19):5259–5271. CrossRefPubMedGoogle Scholar
  15. 15.
    Huang P, Kishida S, Cao D, Murakami-Tonami Y, Mu P, Nakaguro M, Koide N, Takeuchi I, Onishi A, Kadomatsu K (2011) The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma. Cancer Res 71(8):2938–2948. CrossRefPubMedGoogle Scholar
  16. 16.
    Teitz T, Inoue M, Valentine MB, Zhu K, Rehg JE, Zhao W, Finkelstein D, Wang YD, Johnson MD, Calabrese C, Rubinstein M, Hakem R, Weiss WA, Lahti JM (2013) Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis. Cancer Res 73(13):4086–4097. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    t’ Lam-Boer J, Verhoef C, de Haan AF, Yilmaz M, Punt CJ, Wilt JH, Koopman M (2014) The CAIRO4 study the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer–a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer. CrossRefGoogle Scholar
  18. 18.
    Maroney S, de Paz CC, Reeves ME, Garberoglio C, Raskin E, Senthil M, Namm JP, Solomon N (2018) Benefit of surgical resection of the primary tumor in patients undergoing chemotherapy for stage iv colorectal cancer with unresected metastasis. J Gastrointest Surg 22(3):460–466. CrossRefPubMedGoogle Scholar
  19. 19.
    Amar S, Roy V, Perez EA (2009) Treatment of metastatic breast cancer: looking towards the future. Breast Cancer Res Treat 114(3):413–422. CrossRefPubMedGoogle Scholar
  20. 20.
    De Bernardi B, Mosseri V, Rubie H, Castel V, Foot A, Ladenstein R, Laureys G, Beck-Popovic M, de Lacerda AF, Pearson AD, De Kraker J, Ambros PF, de Rycke Y, Conte M, Bruzzi P, Michon J, Group SEN (2008) Treatment of localised resectable neuroblastoma Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br J Cancer 99(7):1027–1033. CrossRefGoogle Scholar
  21. 21.
    Modak S, Kushner BH, LaQuaglia MP, Kramer K, Cheung NK (2009) Management and outcome of stage 3 neuroblastoma. Eur J Cancer 45(1):90–98. CrossRefPubMedGoogle Scholar
  22. 22.
    Chiarella P, Bruzzo J, Meiss RP, Ruggiero RA (2012) Concomitant tumor resistance. Cancer Lett 324(2):133–141. CrossRefPubMedGoogle Scholar
  23. 23.
    Franco MBO, di Gianni PD, Goldman A, Pasqualini CD, Ruggiero RA (1996) A serum-mediated mechanism for concomitant resistance shared by immnogenic and non-immnogenic murine tumors. Br J Cancer 74(2):178–186. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ruggiero RA, Bruzzo J, Chiarella P, di Gianni P, Isturiz MA, Linskens S, Speziale N, Meiss RP, Bustuoabad OD, Pasqualini CD (2011) Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance. Cancer Res 71(22):7113–7124. CrossRefPubMedGoogle Scholar
  25. 25.
    Ehrlich P, Apolant H (1906) Experimentelle carcinomstudien an Mäusen. Arbeiten aus dem Koiglichen Institut fur Experimentelle Therapie zu Frankfurt/AM. Jena, Germany. Gustav FischerGoogle Scholar
  26. 26.
    Demicheli R, Miceli R, Moliterni A, Zambetti M, Hrushesky WJ, Retsky MW, Valagussa P, Bonadonna G (2005) Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol 16(9):1449–1457. CrossRefPubMedGoogle Scholar
  27. 27.
    Kaya M, Wada T, Nagoya S, Kawaguchi S, Isu K, Yamashita T (2004) Concomitant tumour resistance in patients with osteosarcoma. J Bone Joint Surg British 86-B(1):143–147. CrossRefGoogle Scholar
  28. 28.
    Bashford E (1910) The immunity reaction to cancer. Proc R Soc Med 3:69–81PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Maho Inoue
    • 1
    • 2
    Email author
  • Yoshiki Tsuchiya
    • 1
  • Nobuya Koike
    • 1
  • Yasuhiro Umemura
    • 1
  • Hitoshi Inokawa
    • 1
  • Yuichi Togashi
    • 2
  • Junnosuke Maniwa
    • 2
  • Mayumi Higashi
    • 2
  • Shigehisa Fumino
    • 2
  • Tatsuro Tajiri
    • 2
  • Kazuhiro Yagita
    • 1
  1. 1.Department of Physiology and Systems BioscienceKyoto Prefectural University of MedicineKyotoJapan
  2. 2.Department of Pediatric SurgeryKyoto Prefectural University of MedicineKyotoJapan

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