Lack of transforming growth factor-beta 1 expression in benign skin tumors of p53null mice is prognostic for a high risk of malignant conversion

Abstract

Expression of transforming growth factor beta 1 (TGF beta 1) protein was examined in chemically induced benign skin tumors with genetically defined empirical risks for malignant conversion. Benign tumors induced in mice which have both alleles of the p53 gene deleted have a malignant conversion frequency of approximately 50%, whereas similar tumors induced in wildtype and heterozygous p53 mice have conversion probabilities of 3 and 8%, respectively (Kemp et al., Cell, 74: 813-822, 1993). The TGF beta 1 antibody, anti-CC (1-30-1), was shown to stain either the proliferative keratinocyte compartment of the tumor or the tumor stroma, whereas another TGF beta 1 antibody, anti-LC (1-30-1), stained highly differentiated granular cells of the tumors. A strong correlation was found between staining of the proliferative keratinocyte compartment of tumors with the anti-CC (1-30-1) antibody and tumor genotype. Only 18% (6 of 32) of homozygous p53 null tumors showed any basal keratinocyte staining with this antibody, whereas over 80% (32 of 38) of heterozygous and wild-type tumors showed positive staining. Additionally, in most tumors examined, the spatial distribution of staining for the proliferating cell nuclear antigen appeared to be mutually exclusive with that of TGF beta 1 on adjacent serial sections. This suggests that, in these cases, tumor keratinocytes are sensitive to negative growth regulation by TGF beta. TGF beta 1 protein staining in benign tumors is thus prognostic for a low probability of malignant conversion, and its expression may be mechanistically involved in limiting malignant conversion since, at the benign tumor stage examined, keratinocytes are still sensitive to growth inhibition by TGF beta 1.