Cancers arise through accumulation of mutations by a somatic cell that disrupt the mechanisms controlling their proliferation, death, differentiation, metabolism and interactions with other tissues. All these processes are regulated by extracellular signals, effectively rendering somatic cells completely dependent upon their somatic environment for expansion, location and survival. Oncogenic mutations preternaturally activate the signaling pathways that convey information provided by these extracellular signals, so short-circuiting the dependence of somatic cells on their environments. In cancers, such rogue cells expand uncontrollably at the expense of their organismal host, disrupting the functions and integrity of normal tissues. Most adult animals are short-lived and post-mitotic, so the emergence of mutant cells is not a significant problem. By contrast, cancer is an ever-present threat for large, long-lived regenerative metazoans like vertebrates: our somatic cells possess all the ingredients for the expeditious evolution of fitter and faster growing variants: significant rates of mutation that drive variation, strong selection in an environment where most cells are arrested or doomed to die, prodigious numbers (1011-1016 depending on the organism) and plenty of time. Despite this, pathological cancers arise in only 1 in 3 individuals during the entire course of their lives. It is believed that cancers are so rare because tumors require multiple, complementary mutations that each deregulate distinct processes, such as proliferation, survival, migration, increased metabolism, stromal remodeling and angiogenesis. Acquisition of so many independent mutations in any one cell is a protracted and unlikely. It is also thought that cancers are pro-actively suppressed by tumor suppressors, proteins that mend or ablate nascent cancer cells. However, these two seemingly simple explanations raise two vexing questions. First, if so many distinct processes have to activated for tumor growth, how is it so easy for normal tissues to do all the same things during development and embryogenesis. Second, tumor suppression is an evolutionarily recent requirement of long-lived animals yet almost all vertebrate tumor suppressors are variants of ancient genes that evolved to respond to damage, stress or checkpoints. How do vertebrate tumor suppressors discriminate between tumor cells, where they act, and normal proliferating cell, where they do not. Answers to these two questions are emerging and shedding much light on the architecture of cell and tissue growth.

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