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Multistage tumor promotion in skin.
Princess Takamatsu Symposia
|January 1, 1983
Summary
Modified phorbol esters disarm tumor promotion, separating skin cancer development into two stages. Stage 1 involves irreversible changes, while Stage 2 with RPA induces papillomas, potentially via prostaglandin F2 alpha.
Area of Science:
- Carcinogenesis
- Dermatology
- Molecular Biology
Background:
- Phorbol esters like 12-O-tetradecanoylphorbol-13-acetate (TPA) are potent skin tumor promoters.
- Modifying the fatty acid chain of TPA can abolish its tumor-promoting efficacy.
- Understanding the stages of skin tumor promotion is crucial for prevention and treatment.
Purpose of the Study:
- To investigate the two-stage process of skin tumor promotion using modified phorbol esters.
- To elucidate the mechanisms underlying the irreversible changes in Stage 1 of tumor promotion.
- To identify key mediators involved in the conversion of initiated cells to a neoplastic phenotype.
Main Methods:
- Synthesis and application of
Main Results:
- Introduction of conjugated double bonds into TPA abolished tumor promoting efficacy but retained hyperplastic and irritant activities.
- A two-stage promotion process was identified using disarmed phorbol esters like 12-O-retinoylphorbol-13-acetate (RPA).
- Stage 1 involves an irreversible change in skin, potentially linked to neoplastic phenotype expression, independent of protein kinase C or superoxide radicals.
- Indomethacin inhibited Stage 1, an effect overcome by prostaglandin F2 alpha (PGF2 alpha), which accumulated post-TPA treatment.
- RPA did not induce prostaglandin accumulation, suggesting PGF2 alpha's role in Stage 1.
Conclusions:
- Skin tumor promotion can be divided into two distinct stages.
- Stage 1 involves a PGF2 alpha-mediated metaplastic process, possibly hijacking the wound response pathway, leading to neoplastic phenotype expression.
- Disarmed phorbol esters are valuable tools for dissecting the mechanisms of carcinogenesis.