Current therapeutic regimens have failed to decrease the high (80 to 90%) mortality rate of neuroblastoma, indicating the need for new therapeutic approaches. Crucial to any approach to therapy is the knowledge of the cell biology of neuroblastoma. One important characteristic of this tumor, both in the patient and in tissue culture, is its marked cellular heterogeneity. Previous and current studies show that many neuroblastoma cell lines comprise two or more cell types: neuroblastic (N) cells which contain neurofilaments and noradrenergic properties (enzymes, uptake mechanisms, and receptors) and substrate-adherent (S), non-neuronal cells with enzymes, intermediate filaments, cell surface antigens, and extracellular matrix (ECM) proteins characteristiC Of embryonic mesectodermal (glial/melanocytic/meningeal) cells. Recently identified intermediate (I) cells share properties of both N and S cells and may represent either a stem cell or a transitional cell between N and S. Important findings related to this cellular heterogeneity are: (i) N and S cells undergo bidirectional phenotypic interconversion (transdifferentiation); (ii) morphological, biochemical, and cell surface antigen changes in N/S interconversion are tightly coordinated, suggesting that this process is controlled by one or very few regulatory genes; and (iii) N cells are highly tumorigenic whereas S cells are non-tumorigenic. Two other pediatric tumors, Ewing's sarcoma and peripheral neuroepithelioma, appear neuroectodermal in origin and comprise N- and S-like cells. Proposed aims are to: (1) quantitate expression (and gene copy number) in N and S cells of oncogenes N-myc and Ha-ras, EGF and NGF receptor and TGF alpha, cell surface antigens, and gangliosides by molecular hybridization and/or immunochemical techniques as a means of distinguishing correlates of both differentiation state and transformation state; (2) examine effects of several soluble-, growth and differentiation factors (e.g., retinoic acid and cyclic AMP) as a means of experimentally inducing differentiation; (3) study t-role of the ECM and cell-cell interactions in N/S interconversion, in an attempt to identify extrinsic signal(s) regulating differentiation or transdifferentiation in clonal cell lines; and (4) determine whether tumors in vivo contain counterparts of the S observed in cell culture to evaluate the prevalence of N/S transdifferentiation in cal neuroblastoma. The current aims represent a continuing effort to define mechanisms underlying transdifferentiation and transformation in human neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA041520-04
Application #
3182078
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-09-01
Project End
1994-06-30
Budget Start
1989-09-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Singh, Pratima K; Gutmann, David H; Fuller, Christine E et al. (2002) Differential involvement of protein 4.1 family members DAL-1 and NF2 in intracranial and intraspinal ependymomas. Mod Pathol 15:526-31
Ross, R A; Lazarova, D L; Manley, G T et al. (1997) HuD, a neuronal-specific RNA-binding protein, is a potential regulator of MYCN expression in human neuroblastoma cells. Eur J Cancer 33:2071-4
Spengler, B A; Lazarova, D L; Ross, R A et al. (1997) Cell lineage and differentiation state are primary determinants of MYCN gene expression and malignant potential in human neuroblastoma cells. Oncol Res 9:467-76
Ross, R A; Spengler, B A; Domenech, C et al. (1995) Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth Differ 6:449-56
Biedler, J L (1994) Drug resistance: genotype versus phenotype--thirty-second G. H. A. Clowes Memorial Award Lecture. Cancer Res 54:666-78
Melino, G; Annicchiarico-Petruzzelli, M; Piredda, L et al. (1994) Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells. Mol Cell Biol 14:6584-96
Biedler, J L; Spengler, B A (1994) Reverse transformation of multidrug-resistant cells. Cancer Metastasis Rev 13:191-207
Rettig, W J; Garin-Chesa, P; Healey, J H et al. (1993) Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res 53:3327-35
Hanada, M; Krajewski, S; Tanaka, S et al. (1993) Regulation of Bcl-2 oncoprotein levels with differentiation of human neuroblastoma cells. Cancer Res 53:4978-86
Rettig, W J; Garin-Chesa, P; Healey, J H et al. (1992) Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci U S A 89:10832-6

Showing the most recent 10 out of 14 publications