Mechanisms of bone invasion and metastasis in human neuroblastoma

Sohara, Yasuyoshi; Shimada, Hiroyuki; DeClerck, Yves A.

doi:10.1016/j.canlet.2005.01.059

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Volume 228, Issue 1 , Pages 203-209, 18 October 2005

Mechanisms of bone invasion and metastasis in human neuroblastoma

Yasuyoshi Sohara
- Division of Hematology–Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Hiroyuki Shimada
- Department of Pathology, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Yves A. DeClerck
- Division of Hematology–Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Biology, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
- Corresponding author. Address: Division of Hematology–Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. Tel.: +1 323 669 411; fax: +1 323 664 9455.

Received 2 December 2004; accepted 12 January 2005.

Abstract

Bone is the second most common site of metastasis in neuroblastoma. Over the last several years, our understanding of the mechanism of bone metastasis in neuroblastoma has significantly improved. Like breast cancer and myeloma, neuroblastoma cells activate osteoclasts to form osteolytic lesions. Activation occurs via the receptor activator of NFκB ligand (RANKL) or in the absence of RANKL via activation of bone marrow mesenchymal stem cells and stimulation by these cells of the expression of IL-6, a potent osteoclast activating factor. Several targets for therapeutic intervention can now be identified. Inhibition of osteoclast activation by bisphosphonates has already shown to be effective in preclinical models of neuroblastoma bone metastasis and should now be tested in phase I clinical studies. Inhibition of RANKL and IL-6 are other potential targets that require preclinical studies before being tested in patients. This article provides a review of our current understanding of the mechanisms involved in bone metastasis in neuroblastoma and discusses how this knowledge is leading to the identification of new targets for therapeutic intervention.

Keywords: Neuroblastoma, Bone metastasis, Bone marrow mesenchymal stem cells, Bisphosphonates, IL-6