title: Is cancer really a 'local' cellular clonal disease?
abstract: Cancer is not simply the result of specific genetic alterations in key regulatory genes, but rather a complex multistep process involving selection of a clonal population of cells. To accumulate three, or often as many as seven, specific mutations in a single cell without incurring a significant number of additional mutations that might lead to cell lethality requires a large number of target cells, some mutagenic activity acting on those target cells for a variable period of time, and efficient selection strategies, which may be to some extent tissue-specific. A number of 'protective' intracellular regulatory circuits might be present in proliferating cells deliberately to protect against carcinogenesis. If it does require some seven sequential carcinogenic 'genetic hits' in a single cellular clone for a malignant tumor to develop, it is mathematically more likely to occur in a tissue with a high background of genetic alterations in neighboring cellular clones, than in a tissue with a low background of such alterations, or with no detectable carcinogenic mutations at all. In this context, the old 'field cancerization' theory by Slaughter and the more recent 'multistep carcinogenesis' model by Fearon and Vogelstein can come together in a single model: 'multistep field cancerization'. This simple conclusion, and our ability to measure 'background carcinogenesis' in different parts of the body, might allow early detection of cancer risk, and eventually help us to develop suitable therapeutic strategies to delay or suppress the carcinogenic process. Molecular technologies are just beginning to be sufficiently sensitive to start testing the hypothesis.
authors.affiliation: Hospital General of Granollers, Granollers, Barcelona, Spain. bronchud@abaforum.es
authors.forename: M H
authors.initials: MH
authors.lastname: Bronchud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002648:Child; D002999:Clone Cells / Q000473:pathology*; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D009857:Oncogenes; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D040901:Proteomics
chemical_list: D016588:Anticarcinogenic Agents