The Clinical Significances of Serum MMP-3, MMP-7, MMP-9 and VEGF-C Levels in Patients with Neuroblastoma

Jun, Ji Eun; Choi, Jae Won; Jung, Hye Lim; Lee, Soo Hyun; Yoo, Keon Hee; Kim, Deok Soo; Shim, Jae Won; Shim, Jung Yeon; Sung, Ki Woong; Koo, Hong Hoe; Park, Moon Soo

Abstract

PURPOSE: Recent investigations have shown that vascular endothelial growth factor-C (VEGF- C) can enhance lymphatic metastasis, and matrix metalloproteinases (MMPs) may act as regulators of angiogenesis and tumor progression in many human cancers of adults. The aim of our study was to evaluate the clinical significances of circulating MMP-3, MMP-7, MMP-9 and VEGF-C in neuroblastoma (NB) which can disseminate by lymphatic and hematogenous spread.
METHODS
Serum levels of MMP-3, MMP-7, MMP-9 and VEGF-C were measured with ELISA assay (R&D system, USA) in 46 NB patients at initial diagnosis and 20 NB patients at relapse, and in 8 healthy children as normal control. Then we analyzed the relationship between the serum levels and clinical parameters: age; gender; primary site; International Neuroblastoma Staging System (INSS) stage; lymph node (LN) and distant organ metastasis; and outcome.
RESULTS
When compared to healthy children, MMP-7 and MMP-9 levels were significantly higher in primary NB (P=0.0077 and P=0.0165). MMP-3, MMP-7 and VEGF-C levels were higher in relapsed patients rather than initially diagnosed patients, but without statistical significances. MMP-3 level was higher in patients older than 2 years but younger than 5 years, and MMP-7 level was higher in patients older than 1 year but younger than 2 years. There were no statistically significant correlation between serum levels of any of four factors and gender nor INSS stages nor primary sites nor N-myc expression nor therapeutic outcome. There was no correlation between serum VEGF-C level and the presence of the LN metastasis in NB, but among the patients with LN metastasis, serum VEGF-C level was higher in patients with regional LN metastasis versus distant LN metastasis (P=0.013). For the relationship with the distant organ metastasis, MMP-3 level was higher in patients with bone, skin and liver metastasis (P=0.012, P=0.010 and P=0.033), and MMP-9 level was higher in patients with lung metastasis (P=0.020).
CONCLUSION
This study showed that circulating level of MMP-3 may be used as a marker for bone, skin and liver metastasis, and MMP-9 as a marker for lung metastasis in NB. Unlike many cancers in adults, circulating level of VEGF-C did not correlate with LN metastasis in NB, but circulating level of VEGF-C may be associated with early phase of lymphatic metastasis. Additional expanded studies are necessary.