Chapter 12: Melanoma and Non-Melanoma Skin Cancer

TUMOR SUPPRESSOR GENES

• Negative cancer regulators

• Cause apoptosis of DNA-damaged cells and block cell division

• Encode cell-cycle regulators, adhesion molecules, DNA repair enzymes, or signal transduction pathway molecules

• p53 most common cancer mutation, present in one-half of all human cancers; ninety percent of squamous cell carcinomas (SCCs) and in most basal cell carcinomas (BCCs) and actinic keratosis (Fig. 12-1)

• PTCH1 member of the patched gene family that acts as a tumor suppressor in BCC.

• CDKN2 mutation of this tumor suppressor leads to familial syndrome of pancreatic cancer and melanoma

• ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

Extrinsic and intrinsic apoptotic pathways

• Lead to the activation of the aspartate-specific cysteine proteases (caspases) that mediate apoptosis

• Extrinsic pathway

  • Involves engagement of particular “death” receptors that belong to the tumor necrosis factor receptor (TNF-R) family (e.g., Fas, DR5, and PERP)

  • Also causes the formation of the death-inducing signaling-complex (DISC)

• Intrinsic pathway

  • Triggered in response to DNA damage

  • Associated with mitochondrial depolarization and release of cytochrome c from the mitochondrial intermembrane space into the cytoplasm

  • Cytochrome c, apoptotic protease-activating factor 1 (APAF-1), and procaspase-9 form a complex termed the apoptosome (caspase-9 is activated and promotes activation of caspase-3, caspase-6, and caspase-7)

• Mutation is not the only way to inactivate tumor suppressor genes; function also can be blocked by methylation of their promoter

ONCOGENES

• Genes with growth-promoting activity

• Proto-oncogene is a normal gene that can become an oncogene due to mutations of increased expression

• Mutated gene causes cellular products to become constitutively active

• Are dominant

• If a normal gene (protooncogene) is present at a locus along with 1 mutated gene (oncogene), the abnormal product takes control

• May derive from viruses (e.g., Src, ras, cmyc)

• Oncogenic NRF2 mutations occur in squamous cell skin cancers

• Human Merkel cell polyomavirus (MCV or MCPyV) is an oncoprotein implicated in the progression of Merkel cell carcinoma (MCC)

CARCINOGENESIS

• Two-hit theory of Knudsen

• First: inheriting a defect in the familial form (5–10% of cancers result from germ-line mutations) or exposure to a carcinogen

• Second: ongoing exposure to the carcinogen that acts as a tumor promoter or cocarcinogen

• Repeated assault on the DNA leads to mutations that cause the cell cycle to lose control

• Mutations from ultraviolet B (UV-B) light cause cytosine (C) to change to thymine (T)

AP-1 (ACTIVATING PROTEIN-1)

• Negative regulator for procollagen transcription; blocked by retinoids

• Collective term referring to dimeric transcription factors composed of Jun, Fos, or ATF subunits (protooncogenes)

• UV-B induces AP-1 binding to DNA at the AP-1-binding site

• AP-1 up regulates mRNA expression for gelatinase and collagenase

• AP-1 blocks collagen gene expression in dermal fibroblasts

• AP-1 proteins regulate the expression and ...