Development of Biological Diversity and Susceptibility to Chemotherapy in Murine Cancer Metastases

We studied the development of biological heterogeneity in a spontaneous melanoma metastasis of clonal origin as demonstrated by karyotypic analysis. The metastatic potential and sensitivity to different chemotherapeutic agents varied both among and within clones of this metastasis isolated either in vitro or in vivo. This finding indicates that, even within a metastasis of clonal origin, cellular heterogeneity for chemotherapy or metastatic potential can develop rapidly and provides a mechanism for the emergence of resistance to therapy. Since most cancer deaths result from metastases that do not respond to treatment, the implications of these findings for the treatment of cancer are clear. Treatment modalities must be designed that circumvent the biological heterogeneity that can develop rapidly within each metastasis and among metastases.