In vitro studies in cell culture have demonstrated the inappropriate expression of the c-sis/PDGF-2(B) proto-oncogene by responsive human malignant cell lines derived from human tumors of mesenchymal origin, such as glioblastomas, fibrosarcomas and osteosarcomas. These findings suggest the possibility that the inappropriate expression of the c-sis proto- oncogene may be part of the mechanisms that lead certain normal cells of mesenchymal origin towards malignancy. These studies were performed in cell culture, in vitro, using established cell lines. We now propose to extend these studies in vivo, in primary human tumors and in primary cell cultures derived from the tumors. We have selected for this purpose primary human astrocytomas which are the focus of ongoing investigations. Our objective is to investigate the expression of PDGF and PDGF receptor genes in these primary tumors, along with the coordinate expression of """"""""progression"""""""" growth factor genes (IGF's, TGF-alpha). In vitro and in vivo studies indicate that PDGF alone cannot adequately account for stimulation of optimal cell growth. The co-ordinate expression of PDGF and """"""""progression"""""""" growth factors may be a necessary step contributing to the development and maintenance of the astrocytoma tumors. Gene expression will be demonstrated using Northern and/or dot blot analysis. Identification of the cells of origin in the primary tumors expressing the genes and their protein products will be accomplished using in situ hybridization and immunocytochemistry. We anticipate that these studies will provide an insight on these important molecular events. Furthermore, they may contribute to new approaches for the detection of astrocytomas, using for this purpose the expression of c-sis mRNA as a molecular probe. Cell heterogeneity of primary cultures derived from the primary tumors and to subclone their heterogeneous cell population; and to correlate the growth characteristics of the subclones with molecular basis for the characterization of cell heterogeneity, using as molecular markers the expression of specific growth factor genes and their protein products. We anticipate that variations in cell types and in their growth characteristics will reflect the expression or co-expression of growth factors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA030101-09A1
Application #
3169047
Study Section
Pathology B Study Section (PTHB)
Project Start
1981-05-01
Project End
1994-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
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Maxwell, M; Galanopoulos, T; Neville-Golden, J et al. (1993) Expression of androgen and progesterone receptors in primary human meningiomas. J Neurosurg 78:456-62
Antoniades, H N; Galanopoulos, T; Neville-Golden, J et al. (1993) Expression of growth factor and receptor mRNAs in skin epithelial cells following acute cutaneous injury. Am J Pathol 142:1099-110
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Chung, C K; Antoniades, H N (1992) Expression of c-sis/platelet-derived growth factor B, insulin-like growth factor I, and transforming growth factor alpha messenger RNAs and their respective receptor messenger RNAs in primary human gastric carcinomas: in vivo studies with in situ hybridiz Cancer Res 52:3453-9
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Antoniades, H N; Galanopoulos, T; Neville-Golden, J et al. (1992) Malignant epithelial cells in primary human lung carcinomas coexpress in vivo platelet-derived growth factor (PDGF) and PDGF receptor mRNAs and their protein products. Proc Natl Acad Sci U S A 89:3942-6
Antoniades, H N (1992) Linking cellular injury to gene expression and human proliferative disorders: examples with the PDGF genes. Mol Carcinog 6:175-81
Yu, X; Dluz, S; Graves, D T et al. (1992) Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc Natl Acad Sci U S A 89:6953-7
Antoniades, H N; Galanopoulos, T; Neville-Golden, J et al. (1992) Expression of insulin-like growth factors I and II and their receptor mRNAs in primary human astrocytomas and meningiomas;in vivo studies using in situ hybridization and immunocytochemistry. Int J Cancer 50:215-22

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