The APC gene can therefore be regarded as an example of a rate-limiting gatekeeper gene that presents an initial barrier to be overcome in the initiation and progression of colon cancer (Kinzler and Vogelstein 1997). In the retina, the Rb cell-cycle regulatory gene appears to play the gatekeeper role (Newsham and others 1998); in sunlight-induced nonmelanoma squamous carcinoma of the skin, p53 plays this role (Brash and others 1991); in breast cancer it might be the Brcal and 2 genes (Couch and Weber 1998); in basal cell cancers it might be the signal-transduction pathway involving genes called "hedgehog" and "smoothened" (Xie and others 1998; Epstein Jr 1996; Johnson 1996). In the progression of stomach cancer, p53 mutations occur earlier than in the small intestine, and tumors with mutations in EGFR-1 are more aggressive than those with p21 (WAF1) mutations. Amplification of c-erbB-2 and of some specific chromosomal regions and loss of heterozygosity in a region containing thymine glycosylase have been reported in stomach cancers.

When a gatekeeper gene can be clearly identified, it should contain mutations or rearrangements that are characteristic of the initiating damage, in that these changes represent some of the earliest genetic events in carcinogenesis. Tissue-specific genes might be similarly involved in the initiation of cancers of lung, stomach, and other tissues by exposure to radon and radon progeny alpha particles. Some of the initial genetic changes resulting from alpha-particle irradiation, such as deletions and rearrangements, are distinctive and might leave characteristic genetic changes, or "fingerprints," on gatekeeper genes and on others activated early by exposures, thus aiding in their identification. But deletions and rearrangements are also common events during tumor progression because of their inherent genomic instability, so alpha-particle fingerprints might be obscured in advanced tumors.

Tumor Growth and Nutrition—The Caterers

Tumors rapidly outgrow the capacity of diffusion from pre-existing blood supplies to provide the oxygen, nutrients, and growth factors required to sustain their growth and expansion. Anoxic regions of tumors that develop far from blood vessels have been shown to contain elevated amounts of p53 indicative of their abnormal state (Graeber and others 1994). Consequently, a critical factor in tumor growth is the capacity to stimulate new blood vessel growth—angiogenesis. Angiogenesis is achieved by a combination of mechanisms. Tumors secrete stimulators of new blood vessel formation (vascular endothelial growth factors) and reduce the presence of inhibitors (Boehm and others 1997; Folkman 1996). Because the growth of new blood vessels involves the proliferation of essentially diploid, normal endothelial cells, these do not exhibit the genomic plasticity of tumor cells and are subject to normal cell regulation. Proliferative endothelial cells exhibit characteristics and gene-expression profiles different from those of



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