Investigations of human platelet-derived growth factor (PDGF) have provided an understanding of at least one mechanism involved in malignant transformation. It is suggested that in vivo, PDGF is delivered during platelet degranulation at the site of injury where it participates in the process of wound healing by stimulating the proliferation and migration of connective tissue cells. We have shown recently that PDGF and the transforming protein of the simian sarcoma virus (SSV) derive from the same or closely related cellular genes. This conclusion is based on the demonstration that PDGF and the SSV-transforming protein share extensive amino acid sequence homology, have common antigenic determinants and structural conformation, and exert identical biological functions. These findings suggest that the ability of the simian sarcoma virus to induce transformation derives from the incorporation of the PDGF gene within the retroviral genome. The resulting transforming onc gene (v-sis) region within the retrovirus genome codes for a PDGF-like mitogen and is capable of inducing neoplastic transformation by the continuous production of this potent mitogen, causing sustained cell proliferation. Consistent with the findings is the detection of v-sis-related messenger RNAs in human tumors of mesenchymal origin. Production of PDGF-like mitogen by these human malignant cells in culture has been established. More recent studies have demonstrated that these cells synthesize, process, and release PDGF-like polypeptides which are recognized by specific PDGF antisera. The partial sequence of c-sis cDNA clones from a human osteosarcoma cell line reveal the sequence identity between the carboxy terminal region of the PDGF-2 chain and the osteosarcoma c-sis gene product. These data provide the first direct demonstration of the presence of c-sis transcripts in a spontaneous human malignant cell line that can potentially be translated to a full-length PDGF-2 precursor protein. These combined findings demonstrate that activation of sis transcription can cause the sustained abnormal proliferation of human cells which are target cells of PDGF action. Thus, sis activation may be involved in the process leading normal cells of mesenchymal origin toward malignancy. (J)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030101-06
Application #
3169051
Study Section
Cognition and Perception Study Section (CP)
Project Start
1981-05-01
Project End
1989-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
Antoniades, H N; Galanopoulos, T; Neville-Golden, J et al. (1994) p53 expression during normal tissue regeneration in response to acute cutaneous injury in swine. J Clin Invest 93:2206-14
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
Graves, D T; Barnhill, R; Galanopoulos, T et al. (1992) Expression of monocyte chemotactic protein-1 in human melanoma in vivo. Am J Pathol 140:9-14
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
Maxwell, M; Galanopoulos, T; Neville-Golden, J et al. (1992) Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799-804
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

Showing the most recent 10 out of 26 publications