Surface antigens of cell subpopulations in prenatal rat brain are expressed in a characteristic non-random pattern on their ethylnitrosourea-induced malignant counterparts

Abstract

Selective induction of neural tumors in the rat by single-dose exposure of the immature nervous system to ethylnitrosourea (EtNU) is a model for the study of cell lineage-, differentiation stage-, and carcinogen-dependent mechanisms in neuro-oncogenesis. Overall yields and relative frequencies of different types of neural tumors vary with the developmental window chosen for the EtNU-pulse. Precursor cells belonging to different neural lineages and targeted by the carcinogen at distinct developmental stages may thus bear a differential risk of malignant conversion. To specify subpopulations of neural precursors in fetal (prenatal day 18) BDIX-rat brain, four monoclonal antibodies (mAbs) recognizing cell surface differentiation antigens were used: mAb RB 13-2 directed against 0-acetylated gangliosides and binding to approximately 36% of fetal brain cells (FBC); mAb RB 13-6 recognizing a 130 kDa glycoprotein (expressed by approximately 8% of FBC); and mAbs RB21-7 and RB21-15 which bind, respectively, to embryonal neural cell adhesion molecules (N-CAM) and a 24 kDa protein (expressed by approximately 55% and 12% of FBC). Antigen expression profiles were compared with those of 14 primary brain tumors and 16 malignant neural cell lines, all of which had been induced by EtNU on prenatal day 18 in vivo. Monoclonal antibodies RB13-2 and RB21-7 did not bind to any of the tumors or cell lines. In contrast, mAbs RB13-6 and RB21-15 both reacted with 14/14 tumors, and with 16/16 and 10116 cell lines, respectively. Expression of the latter antigens might thus specify lineage-specific stages of FBC development/differentiation particularly susceptible to EtNU-induced malignant transformation. Two-color fluorescence analyses revealed three subsets of FBC binding mAb RB13-6 (RB13-2+/ RB13-6+/ RB2 1-1 5-; RB 13-2-mB 13-6+mB2 1-1%; and RB 13-2-/

Neural cell surface differentiation antigen gp130RB13‐6induces fibroblasts and glioma cells to express astroglial proteins and invasive properties

“…The induction of invasiveness into collagen I supports the assumption that gp130 RB13-6 is an important factor in the process of glial cell differentiation, which is accompanied by the migration of glial precursors from the ventricular germinal layers to their final destinations in the intermediate or mantle zone and other extraventricular sites (2). This motility-stimulating function of gp130 RB13-6 provides an obvious explanation for the observations that the expression of gp130 RB13-6 is a characteristic of the malignant phenotypes resulting from EtNU-induced neurooncogenesis in the rat (5,6).…”

“…The molecular mechanisms underlying the initiation and execution of the astrocyte/Schwann cell differentiation program are insufficiently defined. gp130 RB13-6 is a candidate molecule in this control cascade because it is transiently expressed by a small subset of neural precursor cells during nervous system development (4,5). It is interesting that expression of gp130 RB13-6 is also a phenotypic trait of neuroectodermal rat tumors induced by EtNU (6).…”

“…FCM analyses were performed as previously described (4,5). Enrichment of gp130 RB13-6 -positive cells after transfection was performed by fluorescence-activated cell sorting.…”

“…In these zones, glioblast derived from neuroepithelial germinal cells begin their migration to extraventricular sites and give rise to the different types of glial cells. gp130 RB13-6 -expressing precursor cells are considered targets for the carcinogen N-ethyl-N-nitrosourea (EtNU); indeed, most neuroectodermal tumors induced by EtNU in the rat express this antigen (5,6). cDNA cloning (7) has identified gp130 as a member of a new protein family of phosphodiesterases/nucleotide pyrophosphatases (PDEs) (reviewed in ref 8) that includes PC-1 (9,10) and the tumor cell motility-stimulating exophosphodiesterase autotaxin (ATX) (11, 12; Fig.…”

A new theory of tumours and tumorigenesis

“…There exist certain 'extreme' types of tumour cells that have changed so that they can be considered to be qualitatively different from their normal counterparts; most research has concentrated on these cells. I have worked, for instance, with a certain tumour cell line transformed by a pulse of EtNU (Kindler-Rohrborn et al, 1994) so tumorigenic that only one cell of this cell line transplanted into a host will subsequently kill the host. But it has been demonstrated, for example, for (normal) embryonic stem (ES) cells, that depending on the number of ES cells transplanted into rat brains, they either produce a tumour or differentiate into neuronal cells (Vogel, 2002).…”