Oncogene activation and tumor progression.

25 years ago (1) Leslie Foulds formulated a number of 'rules' for tumor progression, the process whereby 'tumors go from bad to worse', in Peyton Rous' original description (2). These rules are equally pertinent today and accessible to analysis by the powerful tools of modem biology. Foulds dissected the malignant phenotype into 'unit characteristics', such as growth rate, invasiveness, metastasizability, hormone dependence, etc. In his own words (3): 'the behavior of tumors is determined by numerous characters that, within wide limits, are independently variable, capable of different combinations and assortments and liable to independent progression'. This explains the biological individuality of tumors. No two tumors are exactly alike, even if induced by the same agent and in the same type of target cells of the same inbred host genotype. Foulds pointed out the need for 'particularization or factorial analysis' (4). Foulds' definition of the 'unit characteristics' reflects his working area, experimental pathology. While it was mainly based on the studies of murine tumors, his examples also included human tumors. He emphasized the independent change of metastasizability and hormone responsiveness in human prostatic and thyroid carcinomas and the stepwise changes in the invasiveness of cervical, gastrointestinal and bladder carcinomas. In the mouse system, the possibility of maintaining the tumor beyond the lifespan of the host revealed that progression does not reach an endpoint in the primary host. With the passage of tumor cell populations, new opportunities are created for further microevolutionary changes. They lead to increased independence from local, systemic or drug induced growth restrictions.