Up- and down-regulation of granulocyte/macrophage-colony stimulating factor activity in murine skin increase susceptibility to skin carcinogenesis byindependent mechanisms

The role of granulocyte-macrophage colony-stimulating Factor (GM-CSF) in tu morigenesis is complex. On the one hand, Chl-CSF can promote tumor cell gro wth, survival, and even metastasis, On the other hand, it can stimulate tum or cell rejection. In skin, it is early expressed after topic application o f tumor-promoting agents and therefore mag be responsible for changes that correlate with skin tumor promotion (e.g., epidermal hyperproliferation and inflammation). To analyze GM-CSF function in skin tumorigenesis. we genera ted transgenic mice epidermally overexpressing tither GR I-CSF or a GM-CSF antagonist, Both types of transgenic mice exhibited significantly increased numbers of benign tumors in a two-step skin carcinogenesis experiment usin g 7',12'-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecano ylphorbol-13-acetate as tumor promoter. However, only animals expressing GM -CSF displayed a significantly elevated carcinoma burden following a single -step carcinogenesis protocol consisting of tumor initiation only. Therefor e, endogenous promotion is responsible for elevated tumor development in GM -CSF-overexpressing mice. In antagonist transgenic animals, an increased tu morigenicity of modified B16 tumor cells after cutaneous transplantation as compared with nontransgenic or GM-CSF transgenic mice was observed. Thus, the antitumor activity leading to the repression of tumor cell growth in co ntrol mire is GM-CSF dependent and is compromised in mice expressing the an tagonist, We suggest that both, up-regulation and down-regulation of GM-CSF activity in skin, increase the incidence and growth of tumors via two inde pendent mechanisms: endogenous tumor promotion in the case of increased GM- CSF activity and compromised tumor cell rejection in the case of decreased GM-CSF activity.