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Role of genes for normal growth factors in human malignancy
S A Aaronson1, H Igarashi, C D Rao
1Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
The human homologue of the v-sis oncogene encodes one chain of human platelet-derived growth factor (PDGF-2). Previous studies have shown that expression of the coding sequence for this growth factor induces malignant transformation of NIH/3T3 cells. We demonstrate the detection of sis/PDGF-2 products indistinguishable from functional PDGF-2 homodimers in human tumor cells. These findings support the concept that expression of the sis/PDGF-2 product in human cells responsive to its proliferative actions can be an important step in the processes leading to malignancy. Unlike sis/PDGF-2, which remains tightly cell-associated, another growth factor, termed transforming growth factor alpha (TGF alpha), is actively secreted. Expression vectors for the TGF alpha coding sequence failed to induce primary transformed foci upon transfection of NIH/3T3 cells despite high levels of TGF alpha synthesized by these cells. Moreover, transfectants selected for secretion of high levels of TGF alpha failed to form colonies on contact inhibited NIH/3T3 monolayers or to induce tumors upon inoculation of nude mice. Thus, the ability of a growth factor to induce autonomous in vitro or in vivo growth is dependent upon more than expression of cognate receptors by the cell in which it is synthesized.
Insights
The sis/platelet-derived growth factor (PDGF-2) is detected in human tumor cells, suggesting its role in malignancy. Transforming growth factor alpha (TGF alpha) expression did not induce tumors, indicating growth factor-induced malignancy depends on more than receptor presence.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- The v-sis oncogene's human homolog encodes platelet-derived growth factor (PDGF-2), a key regulator of cell growth.
- Previous research indicated that PDGF-2 expression can induce malignant transformation in NIH/3T3 cells.
Purpose of the Study:
- To investigate the presence and role of sis/PDGF-2 products in human tumor cells.
- To compare the oncogenic potential of cell-associated sis/PDGF-2 with secreted transforming growth factor alpha (TGF alpha).
Main Methods:
- Detection of sis/PDGF-2 products in human tumor cells.
- Transfection of NIH/3T3 cells with expression vectors for TGF alpha coding sequences.
- Assessment of colony formation in contact-inhibited monolayers and tumor induction in nude mice for TGF alpha transfectants.
Main Results:
- sis/PDGF-2 products, identical to functional PDGF-2 homodimers, were detected in human tumor cells.
- Expression of TGF alpha coding sequences did not induce primary transformed foci in NIH/3T3 cells.
- NIH/3T3 cells secreting high levels of TGF alpha failed to form colonies or induce tumors in vivo.
Conclusions:
- The presence of sis/PDGF-2 in human tumor cells supports its role in malignancy, particularly in cells responsive to its proliferative signals.
- The inability of TGF alpha to induce autonomous growth suggests that malignancy induction by growth factors is a complex process.
- Autonomous growth in vitro or in vivo is not solely dependent on the expression of cognate receptors by the producing cell.