The Evolution of Explanatory Models of Cancer

Abstract

Since the 1970s, the origin of cancer is being explored from the point of view of genetic mutations and clonal expansion of somatic cells. As cancer research expanded in several directions, while the dominant focus on cells remained steady, more and more classes of genes and kinds of extra-genetic factors that were shown to have causal relevance in the onset of cancer. The wild heterogeneity of cancer-related mutations and phenotypes, along with the increasing complication of models, led to the oscillation recently described by Robert Weinberg between, on one hand, the hectic search of “the” few key factors that cause cancer, and, on the other hand, the discouragement in face of a seeming “endless complexity”. In this chapter, employing the consolidated strategy of ‘key models’, I review the evolution of explanatory models of cancer, from the Clonal Genetic Model to the Stochastic Model and the Multigenic Multiphasic Model of Cancer (combining Oncogenes and Tumor Suppressor Genes); I illustrate the importance of epigenetics in the Epigenetic Progenitor Model of Cancer, and the idea of Cancer Stem Cells in the Hierarchical Model of Cancer. I also review the Evolutionary Argument for carcinogenesis, and I confront the endurance of a more and more complicated Cell-Centred Perspective with the multiplicity of causes and with complex causality (i.e., the coexistence of different modes of causation interacting in a temporal dynamics).