Abstract
Objects
To improve the therapy of advanced neuroblastoma (NB), it is critical to develop animal models that mimic NB bone metastases. Unlike the human disease, NB xenograft models rarely metastasize spontaneously to bone from the orthotopic site of primary tumor growth.
Methods
Single-cell suspensions of SY5Y, KCNR NB cells were injected directly into the femur of nude mice. Radiological and histological analyses and immunohistochemistry analyses were performed to characterize these osseous NB models. SY5Y and KCNR result in osteolytic responses.
Results
We have detected osteoprotegerin, receptor activator of nuclear factor kappa B ligand, parathyroid hormone-related protein, and endothelin-1, proteins associated with bone growth and osteolysis, and C-X-C chemokine receptor type 4 (CXCR4) involved in tumor growth and tumor cell migration in the NB cells grown in the bone.
Conclusions
These animal models can be used to study biological interactions, pathways, and potential therapeutic targets and also to evaluate new agents for treatment and prevention of NB bone metastasis.
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References
Ara T, DeClerck YA (2006) Mechanisms of invasion and metastasis in human neuroblastoma. Cancer Metastasis Rev 25:645–657
Bilir A, Erguven M, Yazihan N, Aktas E, Oktem G, Sabanci A (2010) Enhancement of vinorelbine-induced cytotoxicity and apoptosis by clomipramine and lithium chloride in humanneuroblastoma cancer cell line SH-SY5Y. J Neurooncol 100:385–395
Carlisle AJ, Lyttle CA, Carlisle RY, Maris JM (2009) CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation. Mol Cancer 8:126
Dickey A, Schleicher S, Leahy K, Hu R, Hallahan D, Thotala DK (2011) GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. J Neurooncol 104:145–153
Dubois SG, Kalika Y, Lukens JN, Brodeur GM, Seeger RC, Atkinson JB, Haase GM, Black CT, Perez C, Shimada H, Gerbing R, Stram DO, Matthay KK (1999) Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21:181–189
Feng C, Zuo Z (2012) Regulatory factor X1-induced down-regulation of transforming growth factor β2 transcription in human neuroblastoma cells. J Biol Chem 287:22730–22739
Granchi D, Corrias MV, Garaventa A, Baglìo SR, Cangemi G, Carlini B, Paolucci P, Giunti A, Baldini N (2011) Neuroblastoma and bone metastases: clinical significance and prognostic value of Dickkopf 1 plasma levels. Bone 48:152–159
Granchi D, Garaventa A, Amato I, Paolucci P, Baldini N (2006) Plasma levels of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in patients with neuroblastoma. Int J Cancer 119:146–151
Hua Y, Gorshkov K, Yang Y, Wang W, Zhang N, Hughes DP (2012) Slow down to stay alive: HER4 protects against cellular stress and confers chemoresistance in neuroblastoma. Cancer. doi:10.1002/cncr.27496
Kroesen M, Lindau D, Hoogerbrugge P, Adema GJ (2012) Immunocombination therapy for high-risk neuroblastoma. Immunotherapy 4:163–174
Li W, Chu Y, Zhang L, Yin L, Li L (2012) Ginsenoside Rg1 prevents SK-N-SH neuroblastoma cell apoptosis induced by supernatant from Aβ(1-40)-stimulated THP-1 monocytes. Brain Res Bull 88:501–506
Ma M, Ye JY, Deng R, Dee CM, Chan GC (2011) Mesenchymal stromal cells may enhance metastasis of neuroblastoma via SDF-1/CXCR4 and SDF-1/CXCR7 signaling. Cancer Lett 312:1–10
Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120
Matthay KK, George RE, Yu AL (2012) Promising therapeutic targets in neuroblastoma. Clin Cancer Res 18:2740–2753
Meier R, Mühlethaler-Mottet A, Flahaut M, Coulon A, Fusco C, Louache F, Auderset K, Bourloud KB, Daudigeos E, Ruegg C, Vassal G, Gross N, Joseph JM (2007) The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion. PLoS One 2:e1016
Owens C, Irwin M (2012) Neuroblastoma: the impact of biology and cooperation leading to personalized treatments. Crit Rev Clin Lab Sci 49:85–115
Park JR, Eggert A, Caron H (2008) Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am 55:97–120
Patel LR, Camacho DF, Shiozawa Y, Pienta KJ, Taichman RS (2011) Mechanisms of cancer cell metastasis to the bone: a multistep process. Future Oncol 7:1285–1297
Peng H, Sohara Y, Moats RA, Nelson MD Jr, Groshen SG, Ye W, Reynolds CP, DeClerck YA (2007) The activity of zoledronic acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. Cancer Res 67:9346–9355
Poretti A, Grotzer MA (2012) Neuroblastoma with spinal cord compression: is there an emergency treatment of choice? Dev Med Child Neurol 54:297–298
Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 351:195–196
Sartelet H, Durrieu L, Fontaine F, Nyalendo C, Haddad E (2012) Description of a new xenograft model of metastatic neuroblastoma using NOD/SCID/Il2rg null (NSG) mice. In Vivo 26:19–29
Sharp SE, Gelfand MJ, Shulkin BL (2011) Pediatrics: diagnosis of neuroblastoma. Semin Nucl Med 41:345–353
Sohara Y, Shimada H, DeClerck YA (2005) Mechanisms of bone invasion and metastasis in human neuroblastoma. Cancer Lett 228:203–209
Sohara Y, Shimada H, Scadeng M, Pollack H, Yamada S, Ye W, Reynolds CP, DeClerck YA (2003) Lytic bone lesions in human neuroblastoma xenograft involve osteoclast recruitment and are inhibited by bisphosphonate. Cancer Res 63:3026–3031
Sorrentino S, Rosanda C, Parodi S, Rita Gigliotti A, Pasino M, Defferrari R, Paolo Tonini G, De Bernardi B (2012) Cyto-morphologic evaluation of bone marrow in infants with disseminated neuroblastoma. J Pediatr Hematol Oncol 34:154–158
Sun W, Modak S (2012) Emerging treatment options for the treatment of neuroblastoma: potential role of perifosine. Onco Targets Ther 5:21–29
Suva LJ, Washam C, Nicholas RW, Griffin RJ (2011) Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol 7:208–218
Ishola TA, Chung DH (2007) Neuroblastoma. Surg Oncol 16:149–156
van Golen CM, Schwab TS, Kim B, Soules ME, Su Oh S, Fung K, van Golen KL, Feldman EL (2006) Insulin-like growth factor-I receptor expression regulates neuroblastoma metastasis to bone. Cancer Res 66:6570–6578
Yang S, Zheng J, Ma Y, Zhu H, Xu T, Dong K, Xiao X (2012) Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy. Oncol Rep 28:186–192
Zhang L, Yeger H, Das B, Irwin MS, Baruchel S (2007) Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. Neoplasia 9:36–46
Acknowledgments
This work was supported by National Natural Science Foundation grant from China National Science Foundation Committee (project code 81172410).
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Zhao, H., Cai, W., Li, S. et al. Establishment and characterization of xenograft models of human neuroblastoma bone metastasis. Childs Nerv Syst 28, 2047–2054 (2012). https://doi.org/10.1007/s00381-012-1909-3
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DOI: https://doi.org/10.1007/s00381-012-1909-3