The somatic mutation theory has been the prevailing paradigm in cancer research for the last 50 years. Its premises are: (1) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations, (2) the default state of cell proliferation in metazoa is quiescence, and (3) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. From this compelling simplicity, an increasingly complicated picture has emerged as more than 100 (...) oncogenes and 30 tumor suppressor genes have been identified. To accommodate this complexity, additional ad hoc explanations have been postulated. After a critical review of the data gathered from this perspective, an alternative research program has been proposed. It is based on the tissue organization field theory, the premises of which are that carcinogenesis represents a problem of tissue organization, comparable to organogenesis, and that proliferation is the default state of all cells. The merits of these competing theories are evaluated herein. BioEssays 26:1097–1107, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous normal cells (...) is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem‐like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of “order in the large over heterogeneity in the small”. BioEssays 28: 515–524, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Despite the spectacular contributions to knowledge made by molecular biology during the last half century, cancer research has not delivered an agreed explanation of how malignant tumours originate. The models assiduously investigated in molecular terms largely reflect waves of fashion, and time has revealed their inadequacy: cancer is (1) not caused by the direct action of oncogenes, (2) not fully explained by the impairment of tumour suppressor genes, (3) not set in motion by mutations controlling the cell cycle, (4) not (...) governed by the dependence of malignant tumours on an adequate blood supply and (5) not triggered by a failure of programmed cell death. But there is now strong evidence that cancers may have their origin in mutations that block the execution of critical steps in the process of normal differentiation. Cancer, thus seen, is not initially a disease of cell multiplication, but a disease of differentiation. The evidence for this point of view should now be explored. BioEssays 27:833–838, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Somatic mutation plays a key role in transforming normal cells into cancerous cells. The analysis of cancer progression therefore requires the study of how point mutations and chromosomal mutations accumulate in cellular lineages. The spread of somatic mutations depends on the mutation rate, the number of cell divisions in the history of a cellular lineage, and the nature of competition between different cellular lineages. We consider how various aspects of tissue architecture and cellular competition affect the pace of mutation accumulation. (...) We also discuss the rise and fall of somatic mutation rates during cancer progression. BioEssays 26:291–299, 2004. © 2004 Wiley Periodicals, Inc. (shrink)