Tumor cell diversity and host responses in cancer metastasis--part II--host immune responses and therapy of metastases.

Recent findings that (1) individual tumor cells in a malignant lesion possess widely different metastatic properties and (2) metastases arise from specific subpopulations of metastatic tumor cells have profound implications for eventually understanding and treating metastatic diseases. These findings have also raised serious doubts concerning the appropriateness of many of the experimental approaches currently in use for studying metastasis. Diversity in metastatic phenotype among cells from the same tumor suggests that the usual analyses of tumor cell lines containing multiple heterogeneous subpopulations may not be fruitful. This is especially true for tumors where the metastatic subpopulations represent only an extremely small fraction of the total number of tumor cell subpopulations. In addition, the screening of potential antitumor and antimetastatic agents for their abilities to inhibit the growth of tumors containing widely heterogeneous subpopulations of metastatic and nonmetastatic cells may not be useful in predicting the efficacy of these treatments against metastases. New methodologies must be developed to isolate and characterize the specific cell subpopulations that possess the metastatic phenotype, with the reservation that careful attention must be paid to the stabilities of these malignant cell subpopulations, especially during long-term growth. Understanding the mechanism(s) controlling the rapid generation of phenotypic diversity in tumor subpopulations, and the regulation of subpopulation diversity during progressive growth of primary and metastatic lesions, is of fundamental importance in the design of experimental systems for studying the metastatic process, and eradicating metastases. This review and its companion, as well as our other recent reviews, have dealt with current information on cancer metastasis and where future efforts might be the most promising in discerning this complex process.