PubMed · 14201593
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M L JANOWER. 1964-11-23. OCCUPATIONAL HAZARD.. https://doi.org/10.1001/jama.1964.03070210075015
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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 NFkappaB 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.
BACKGROUND: There is currently no technique to image quantitatively bone metastases. Here, we assessed the value of MRI of the axial skeleton (AS-MRI) as a single step technique to quantify bone metastases and measure tumor response. METHODS: AS-MRI was performed in 38 patients before receiving chemotherapy for metastatic HRPCa, in addition to PSA, computed tomography of the thorax, abdomen, and pelvis [CT-TAP]; and Tc-99m bone scintigraphy. A second AS-MRI was performed in 20 patients who completed 6 months of chemotherapy. Evaluation of tumor response was performed using RECIST. RESULTS: Only 11 patients (29%) had RECIST measurable metastases in soft-tissues or lymph nodes on baseline CT-TAP. AS-MRI identified a diffuse infiltration of the bone marrow in 8 patients and focal measurable metastatic lesions in 25 patients (65%), therefore, doubling the proportion of patients with measurable lesions. Transposing RECIST on AS-MRI in 20 patients who completed 6 months of treatment, allows the accurate estimation of complete response (n = 2), partial response (n = 2), stable disease (n = 5), or tumor progression (n = 11), as it is done using CT-TAP in soft tissue solid metastases. CONCLUSIONS: MRI of axial skeleton enables precise measurement and follow-up of bone metastases as it is for other soft-tissue metastasis.
Chromosomal translocation t(11; 22)(q24; q12) is detected in approximately 90% of Ewing's family tumors (EFTs) including Ewing's sarcoma and primitive neuroectodermal tumor. This results in the formation of the EWS-Fli1 fusion gene, which produces EWS-Fli1 fusion protein. This chimerical gene product acts as an aberrant transcriptional activator, which may be responsible for the tumorigenesis of EFTs. We have previously reported that cyclin E expression was upregulated in EFT cells and in EWS-Fli1 transformed fibroblastic cells. However, the mechanism of the overexpression of cyclin E by EWS-Fli1 is still unknown. In our study, we investigated the mechanism of transactivation of the cyclin E gene in EFT cells. We found that EWS-Fli1 enhanced the activity of the cyclin E gene promoter partially through E2F binding sites in the promoter. In addition, the basic transcriptional factor, Sp1, might also be involved in the transactivation of the cyclin E gene by EWS-Fli1. To study the biological significance of cyclin E overexpression in EFT cells, we used flavopiridol, a pan-cyclin-dependent kinase (CDK) inhibitor and found that flavopiridol efficiently suppressed the growth of EFT cells in vitro and in vivo by the inhibition of cyclinE/CDK2 kinase activity and the induction of apoptosis. These results suggest that targeting of the cyclin/CDK complex may provide new insight into treatment of EFTs.