Differential expression of delta-like gene and protein in neuroblastoma, ganglioneuroblastoma and ganglioneuroma

Abstract

Neuroblastoma is an extremely malignant solid tumor in children, characterized by spontaneous differentiation and regression. An epidermal growth factor-like homeotic protein, delta-like (dlk), has been involved in differentiation of neuroblastoma cell lines, but is unknown in in vivo expression of neuroblastoma. By using in situ hybridization and immunohistochemistry, dlk mRNA and protein expression were studied in formalin-fixed archival tissues from 10 patients with neuroblastoma, five with ganglioneuroblastoma, and five with ganglioneuroma. Three adrenal tissues from children died of diseases other than adrenal tumors and one from an adult with pheochromocytoma were severed as normal and disease controls. The results showed strong immunoreactive dlk staining in endothelial cells in neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Dlk was detectable in mature neuromatous stroma and gangliocytes of ganglioneuroma, but not in neuroblasts of neuroblastoma and ganglioneuroblastoma, neither in gangliocytes of ganglioneuroblastoma. In contrast, dlk mRNA expression was mainly observed in the gangliocytes, but was less intense in the neuroblasts and neuromatous stroma cells. Endothelial cells were essentially devoid of dlk mRNA expression. The findings indicated that there is differential expression of dlk gene and protein among neuroblastoma, ganglioneuroblastoma and ganglioneuroma. The stronger expression of dlk in gangliocytes in ganglioneuroma, in contrast to weaker or no expression in gangliocytes in ganglioneuroblastoma and neuroblasts in neuroblastoma, suggests upregulation of dlk during differentiation of neuroblastoma into more benign form. Furthermore, higher dlk protein expression in the tumor endothelium than in the endothelium of normal adrenal gland implies that dlk may regulate the endothelial function in neuroblastic tumors.

Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas

“…The staining pattern of DLK on the cells of hepatoblastomas is not uniform, but it is mostly associated with the cell surface. This is in agreement with the fact that DLK is a transmembrane protein with a large extracellular domain, but cytoplasmic staining of DLK also has been reported [8].…”

“…A few other undifferentiated childhood tumours were also tested for this marker, but they were negative except for the large ganglion cells of ganglioneuroblastomas (data not shown) in accordance with a previous report [8]. This is in line with the observation that DLK expression correlates with maturation along the chromaffin lineages [24].…”

DLK is a novel immunohistochemical marker for adrenal gland tumors

“…Thus, the sensitivity of DLK for adult adrenal tumors was 100% while the specificity on our samples was 87%. No neuroblastomas were included in this work, because DLK expression in this group of tumors has been thoroughly analyzed [4]. Neuroblastomas were reported negative while the differentiating cells of ganglioneuromas became positive.…”

“…We have recently described [2] that DLK expression is maintained in the hepatoblasts upon malignant transformation, and it can be applied as a diagnostic immunohistochemical marker for hepatoblastomas. DLK expression has been reported in normal adrenal cortex [3], in ganglioneuroblastomas, in pheochromocytomas, and in other endocrine tumors [4][5][6], but no comprehensive immunohistochemical analysis has been performed on adrenocortical tumors. In this present work, we have collected adrenal gland-derived and differential diagnostically related tumors from our archives and investigated their DLK expression by standard immunohistochemistry.…”

In vivo far-red luminescence imaging of a biomarker based on BRET from Cypridina bioluminescence to an organic dye

“…A monoclonal antibody against human Delta-like protein (Dlk-1), one of the embryonic antigens expressed on the surface of many cancer cells, was then produced (21)(22)(23)(24)(25). Using anti-Dlk-1 monoclonal antibody linked to FBP via biotin-avidin interaction, we achieved bioluminescence imaging of cancer cells in vivo as well as in vitro.…”