Pathogenesis of metastatic disease: Implications for current therapy and for the development of new therapeutic strategies

Different tumor cell subpopulations coexisting within the same tumor exhibit varied susceptibilities to antineoplastic agents. Tumor cell heterogeneity is now recognized as the principal cause of treatment failure in cancer, and is a formidable obstacle to effective therapy and to the development of drug delivery systems for selective targeting of antineoplastic agents to tumor cells. Recent insights into the genesis of tumor cell heterogeneity during progressive tumor growth reveal new complexities that raise challenging questions about the adequacy of certain approaches to the current therapy of metastatic disease and impose challenging criteria for the development of improved therapeutic strategies. Many of the experimental approaches used in the search for new antineoplastic agents and targeted drug delivery systems ignore the pathogenesis of metastasis and the problem of tumor cell heterogeneity. The adoption of more relevant assay systems is an urgent priority. These include the greater use of metastatic tumor models and the increased use of human tumor cells to replace rodent cell systems which have been of limited predictive value in identifying effective anticancer agents. In contrast to current strategies for the development of new antineoplastic drugs which seek to identify agents with activity against a broad range of histologically diverse tumors, greater success may be achieved by seeking agents active only against specific cell lineages. Many established human tumor cell lines may not be suitable for this purpose because of extensive phenotypic change produced by prolonged passage ex vivo. Development of histiotype-specific human tumor cell screens will require an extensive research effort to identify target cells that display demonstrable phenotypic relatedness to tumor cells in neoplastic lesions. Major advances in the therapy of metastatic disease are considered unlikely in the next few years, and progress will stem from improved use of existing agents in refined combination therapy protocols in which greater attention is given to the duration, frequency, and sequence of therapy with different agents to limit emergence of tumor cell variants resistant to one or more antineoplastic agents. Advances in molecular biology offer exciting prospects for the identification of new therapeutic targets in human tumor cells, for the induction of alterations in tumor cells that could serve as therapeutic targets, and for the elucidation of the mechanisms responsible for the rapid phenotypic diversification of tumor cells. These opportunities will not be realized, however, unless more stringent experimental systems are adopted and refined at regular intervals to accommodate new knowledge about the cell biology of metastasis.