Progress in Cutaneous Cancer Research1 Andrzej Dlugosz  Journal of Investigative Dermatology Symposium Proceedings  Volume 7, Issue 1, Pages 17-26 (December 2002) DOI: 10.1046/j.1523-1747.2002.19631.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Genetic changes associated with melanoma progression. The multistage evolution of metastatic melanoma is depicted schematically with frequently associated stage-specific genetic changes detailed below. Trisomy of 7q, detected in invasive vertical growth phase melanoma, would amplify the listed tyrosine kinase receptors (EGFR, c-MET) the ligand HGF, and BRAF, but a causal relation to progression is not proven. The loss of APAF-1 may occur through gene deletion or gene silencing. Journal of Investigative Dermatology Symposium Proceedings 2002 7, 17-26DOI: (10.1046/j.1523-1747.2002.19631.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Proposed model depicting the molecular basis of BCC. In contrast to the multistep evolution of SCC and melanoma, deregulation of the SHH signaling pathway may be sufficient for BCC development. During physiologic activation in responsive cell types, SHH binds and inhibits PTCH1, which normally represses SMO. Derepression of SMO results in transient activation of SHH target genes, including PTCH1, GLI1, and cell type-specific genes, which are likely to play an important role in growth control. In BCC, mutations involving PTCH1 or SMO result in uncontrolled signaling and constitutive expression of SHH target genes. Journal of Investigative Dermatology Symposium Proceedings 2002 7, 17-26DOI: (10.1046/j.1523-1747.2002.19631.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Genetic changes associated with human cutaneous SCC. The multistage evolution of invasive SCC is depicted schematically with frequently associated genetic changes detailed below. Single base mutations in early lesions frequently are characteristic of UV light-induced damage, whereas later changes are associated with genomic instability. Increased activity of telomerase (deletion of inhibitor) or EGFR tyrosine kinase (gene amplification) may also result from epigenetic changes. Journal of Investigative Dermatology Symposium Proceedings 2002 7, 17-26DOI: (10.1046/j.1523-1747.2002.19631.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Genetic changes associated with chemically induced mouse cutaneous SCC. The multistage evolution of anaplastic or spindle cell tumors in this model is highly ordered both temporally and genetically. Ras mutations are characteristic of chemical mutagens used to initiate tumor formation. Early upregulation of cyclin D1 and later up-regulation of TGFα1 occur through epigenetic mechanisms and appear to be important components of carcinogenesis. Journal of Investigative Dermatology Symposium Proceedings 2002 7, 17-26DOI: (10.1046/j.1523-1747.2002.19631.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Stage-specific biologic changes associated with multistage cutaneous carcinogenesis. This scheme is proposed to focus on processes that may be common for multistage tumor development where precise biochemical pathways are still under study. Early events reflect changes occuring in incipient tumor cells whereas progression incorporates processes at the tissue and organismal level that must be addressed to fully comprehend cutaneous cancer pathogenesis. Journal of Investigative Dermatology Symposium Proceedings 2002 7, 17-26DOI: (10.1046/j.1523-1747.2002.19631.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions