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Establishing a link between oncogenes and tumor angiogenesis
R S Kerbel1, A Viloria-Petit, F Okada
1Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada. kerbel@srcl.sunnybrook.utoronto
Abstract:
We have tried to stress that mutant oncogenes or overexpressed, nonmutated proto-oncogenes, in addition to their direct affect on promoting aberrant tumor cell proliferation (and survival), may possess a crucial indirect means of stimulating tumor cell growth through regulation of angiogenesis. This effect would never be observed in tissue culture studies of oncogene function using pure cultures of tumor cells, which probably helps explain why the pro-angiogenic function of oncogenes has not been appreciated until only relatively recently. Indeed, the very first indication of a possible contributory role of oncogenes, such as ras and myc, to tumor angiogenesis was first reported by Thompson et al. in 1989, who used reconstituted organ cultures of the mouse prostate gland for their studies (69). This potentially important contribution of oncogenes to tumor growth and development may prove to have an impact on how various signal transduction inhibitors that are now in early phase clinical trials, e.g., monoclonal neutralizing antibodies to the human EGF receptor (70), function in vivo as anti-tumor agents.
Insights
Oncogenes promote tumor growth not only by direct cell proliferation but also by regulating angiogenesis, a mechanism previously unappreciated in standard cell cultures. This finding impacts the development of targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oncogenes and proto-oncogenes are critical regulators of cell growth and survival.
- Traditional in vitro studies using pure tumor cell cultures have limitations in revealing complex tumor microenvironment interactions.
- The role of oncogenes in tumor angiogenesis has been historically underestimated.
Purpose of the Study:
- To highlight the indirect role of oncogenes in stimulating tumor growth via angiogenesis.
- To explain why this pro-angiogenic function was not readily observed in previous experimental models.
- To underscore the significance of oncogene-driven angiogenesis in cancer development.
Main Methods:
- Utilized reconstituted organ cultures (mouse prostate gland) to study oncogene function in a more complex environment.
- Investigated the effects of oncogenes like ras and myc on tumor angiogenesis.
- Reviewed existing literature and early clinical trial data on signal transduction inhibitors.
Main Results:
- Mutant oncogenes and overexpressed proto-oncogenes can indirectly promote tumor cell growth by regulating angiogenesis.
- Early studies using reconstituted organ cultures provided initial evidence for oncogene involvement in tumor angiogenesis.
- This indirect mechanism is not detectable in standard tissue culture models.
Conclusions:
- Oncogenes play a significant role in tumor development through the regulation of angiogenesis.
- Understanding this indirect mechanism is crucial for developing effective anti-cancer therapies.
- Findings may influence the clinical application of signal transduction inhibitors targeting pathways like EGF receptor.