Rethinking "cancer as a dynamic developmental disorder" a quarter century later

In a Perspectives article of 1985 in Cancer Research, I discussed evidence for a nonmutational origin of teratocarcinoma, and cited related claims in liver carcinogenesis, which I later broadened to include spontaneous transformation in cell culture. Further research on spontaneous transformation cast doubt on that interpretation, and motivated re-examination of the cases for teratocarcinomas and liver cancer. This re-examination led to the conclusion that mutation and selection underlie the development of neoplasia in all three cases. At the same time, it affirmed the primary role of hierarchical tissue structure and intercellular relations in maintaining homeostasis, which was the major theme of the 1985 article. Tumor promotion disrupts intercellular relations to allow progressively selective proliferation of initiated cells and accompanying clonal accumulation of genetic change.