Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

Abstract

The heparin-binding growth factor midkine (MK) is the product of a retinoic acid-responsive gene, and is implicated in neuronal survival and differentiation, and carcinogenesis. We previously reported that MK mRNA expression is elevated in neuroblastoma specimens at all stages, whereas pleiotrophin, the other member of the MK family, is expressed at high levels in favourable neuroblastomas. As MK is a secretory protein, it can be detected in the blood. Here, we show a significant correlation of the plasma MK level with prognostic factors of neuroblastomas. The plasma MK level was determined in 220 patients with neuroblastomas, and compared with that in children without malignant tumors (n ¼ 17, o500 pg ml À1 ). The plasma MK level became significantly elevated with advancing stages (stage 1: 445 pg ml À1 (median), n ¼ 73; stage 2: 589, n ¼ 39; stage 3: 864, n ¼ 40; stage 4: 1445, n ¼ 56; and stage 4S: 2439, n ¼ 12). More importantly, a higher MK level was strongly correlated with poor prognostic factors: over 1 year of age (P ¼ 0.0299), MYCN amplification (Po0.0001), low TrkA expression (P ¼ 0.0005), nonmass screening, sporadic neuroblastomas (Po0.0001), and diploidy/tetraploidy (P ¼ 0.0007). Thus, these results demonstrate that the plasma MK level is a good marker for evaluating the progression of neuroblastomas. Moreover, considering the ability of antisense MK oligodeoxyribonucleotide to suppress tumour growth of colorectal carcinoma cells in nude mice, as recently reported, the present study suggests that MK is a possible candidate molecular target for therapy for neuroblastomas.

Plasma midkine level is a prognostic factor for human neuroblastoma

“…As predicted from our previous data, (15) we found that MK level is correlated with established prognostic factors (MYCN, TRKA, ploidy, stage and age). Since mass screening has been discontinued, sporadic NBL are the major subject of therapy.…”

“…The data indicate close correlations between MK levels and known prognosis factors and are consistent with our previous report. (15) Figure 2(a) shows Kaplan-Meier survival curves based on plasma MK levels for all NBL cases. A high MK level was closely associated with poor prognosis of NBL patients (P < 0.0001), indicating that the MK level alone can be a prognostic factor for NBL patients.…”

“…(13,14) We previously reported that the plasma MK level was correlated with the values of established prognostic factors through a study of 220 cases, including 82 non-mass-screening (sporadic) cases and 122 mass-screening cases. (15) However, in that study, information on the prognosis of patients was too limited to determine whether the plasma MK level could be a prognostic factor. In the present study, we measured plasma MK levels of 756 NBL cases, which consisted of 286 sporadic cases, 387 mass-screening cases and 83 unknown cases.…”

“…The same archive samples were used as those without malignant tumors (n = 17; eleven were <1-year old and six were >1-year old). (15) Enzyme-linked immunoassay for human MK. An enzyme-linked immunoassay for human MK was performed as described previously.…”

Midkine Lacking Its Last 40 Amino Acids Acts on Endothelial and Neuroblastoma Tumor Cells and Inhibits Tumor Development

“…In particular, MDK was shown to correlate with tumor progression and invasiveness of neuroblastoma. Indeed, plasma MDK levels were found to be significantly correlated with the status of N-myc amplification, TRKA expression, and stage, which are known prognostic factors in neuroblastoma (19). In this study, we assessed the effects of the 81-121 deleted MDK (MDKD81-121) lacking its last 40 amino acids, and for the first time, demonstrate that this truncated protein could act as a potent inhibitor of tumor growth and angiogenesis in a neuroblastoma tumor model.…”