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Tumour suppression associated with expression of human insulin-like growth factor II
P N Schofield1, A Lee, D J Hill
1Department of Zoology, University of Oxford, UK.
Abstract:
Recent circumstantial evidence has implicated Insulin-like growth factor II in the genesis of several tumour types, notably developmental tumours (Scott et al., 1985; Schofield & Tate, 1987; Wilkins et al., 1989). This type of tumour, thought to originate during the defective differentiation of organ precursors (Miereau et al., 1987), often expresses greatly elevated levels of mRNA for IGF-II, a known mitogen for these cells and abundantly expressed in their presumed normal counterparts (Scott et al., 1985; Schofield & Tate, 1987; Gray et al., 1987). It has been proposed that continued, inappropriate expression of this gene drives tumour growth by an autocrine mechanism. In order to examine the potential role of IGF-II in the growth of tumour cells an IGF-II cDNA was introduced into a retroviral expression vector, and used to infect a cloned fibroblast cell line. Expression of IGF-II conferred a degree of serum independence of growth in cell culture, however, when cells were injected into nude mice as subcutaneous grafts, clones expressing IGF-II from the retrovirus were found to have a greatly increased (five fold) latency of sarcoma formation. After a prolonged lag all cell lines eventually gave rise to tumours in which the introduced IGF-II genes had either been lost or inactivated, suggesting that in this system IGF-II acts as a tumour suppressor gene.
Insights
Insulin-like growth factor II (IGF-II) may suppress tumour growth, contrary to previous theories. Introducing IGF-II into fibroblasts delayed sarcoma formation in mice, suggesting a tumor suppressor role.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Insulin-like growth factor II (IGF-II) is implicated in developmental tumor genesis.
- Elevated IGF-II mRNA levels are observed in certain tumors, with proposed autocrine growth mechanisms.
- IGF-II is a mitogen for tumor cells and expressed in normal counterparts.
Purpose of the Study:
- To investigate the role of IGF-II in tumor cell growth.
- To determine if IGF-II acts as a tumor promoter or suppressor.
Main Methods:
- Introduced IGF-II cDNA into a retroviral expression vector.
- Infected a cloned fibroblast cell line with the vector.
- Injected modified cells into nude mice to observe tumor formation.
Main Results:
- IGF-II expression conferred serum-independent growth in cell culture.
- Fibroblast clones expressing IGF-II showed a five-fold increased latency in sarcoma formation.
- Tumors eventually formed, but the introduced IGF-II genes were lost or inactivated.
Conclusions:
- IGF-II may function as a tumor suppressor gene in this experimental system.
- The proposed autocrine mechanism for IGF-II in tumor growth may not apply universally.
- Further research is needed to elucidate the complex role of IGF-II in tumorigenesis.