The Ernst W. Bertner Memorial Award lecture: the evolution of biological heterogeneity in metastatic neoplasms.

The complexity of the processes of tumor progression and metastasis makes it difficult to provide generalized rules. Results and hypotheses that are based upon a single tumor system or a simple experimental technique are likely to be revised as more data become available. However, bearing these limitations in mind and ignoring the above warnings, I wish to conclude the following: By the time of diagnosis, many malignant neoplasms are heterogeneous, i.e., they contain subpopulations of cells with different biological characteristics. The process of metastasis involves a sequence of complex events whose outcome depends on tumor cell properties and host factors. The metastatic process selects variants from a heterogeneous starting population. The diversity for the metastatic phenotype may be a consequence of the multicellular origin of a neoplasm or it may be the result of continuous evolution and progression in tumors of unicellular origin. Metastatic clones appear, in general, to be less stable than nonmetastatic clones. Metastatic clones exhibit an increased rate of spontaneous mutation compared with nonmetastatic clones. Some metastases may be clonal in their origin, and multiple metastases can originate from different progenitor cells. Biological diversity can rapidly develop within individual metastases. The acquisition of phenotypic heterogeneity by populations of tumor cells imposes a degree of stability on the tumor as a whole. The generation of biological diversity in malignant neoplasms and within and among metastases has profound implications both for studies on the pathogenesis of cancer metastasis and for the design of any successful approach to the treatment of this disease.