HIF-2α and IGF2 were strongly expressed in subsets of immature neuroblastoma cells, suggesting that these two genes could be co-expressed also at early stages of SNS development.
Here, we present evidence that the expression of IGFBP-5 is a common feature of neuroblastoma cell lines and that IGFBP-5 acts in concert with IGF-2 in inducing cell proliferation.
We investigated the biologic effect of trkA, with special reference to its effect on insulin-like growth factor-II (IGF-II) expression, in SK-N-AS human neuroblastoma cells transfected with human trkA cDNA.
Classic neuroblastoma (NB) and its more highly differentiated stroma-rich subtypes, extra-adrenal sympathetic paraganglioma, and pheochromocytoma were examined for the presence of the developmentally characterized gene products NSE, S-100, CD44, Bcl-2, HNK-1, PNMT, TrkA, IGF2, and tyrosine hydroxylase.
Therefore, IGF-II mediates autocrine proliferation in neuroblastoma cells under the control of IGFBPs secreted by the cells, its bioavailability being enhanced as a result of plasmin-induced IGFBP-2 proteolysis.
These data suggest that the expression of IGF-II is not confined to a specific stage of the disease but may have a broader role in the pathogenesis of neuroblastoma.
The similarities found between IGF2-expressing neuroblastoma cells and paraganglia/SIF cells in terms of histological features, anatomical origin, and age-dependent growth suggest a paraganglionic/SIF cell lineage of most infant tumors and also of extra-adrenal tumors diagnosed after infancy.
We postulated that the pathogenesis of her hypoglycemia involved production of IGF-II by her neuroblastoma, leading to GH suppression and an abnormally elevated ratio of IGF to IGF binding protein.
The SH-SY5Y human neuroblastoma cell line also expresses IGF-II and its receptors and responds to exogenous IGF-II with increased DNA synthesis, cell division, and neuritic outgrowth.
A RA dose response test indicates that an increase in IGF-II mRNA occurs within 2 days in SH cells treated with doses of RA from 1 x 10(-8) to 1 x 10(-5) M. We suggest that IGF-II expression may be regulated either directly or indirectly by RA in vitro and may lead to neuroblastoma differentiation.
An examination of human neuroblastoma tumor tissues for IGF-II gene expression using in situ hybridization histochemistry revealed that IGF-II is expressed by tumor cells in only 5 of 21 neuroblastomas, but is detectable in cells of nonmalignant tissues including adrenal cortical cells, stromal fibroblasts, and eosinophils in all 21 tumors.
Furthermore, inasmuch as all neuroblastoma (12 of 12) cell lines examined expressed IGF-II RNA, the pattern of IGF expression could distinguish between these closely related tumors.