The major cause of death from cancer is due to metastases that are resistant to conventional therapies. Several reasons account for the failure to treat metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects for a small subpopulation of cells that preexist within a parental neoplasm. Third, and perhaps the greatest obstacle for therapy, is that the outcome of metastasis depends on multiple interactions ('cross-talk') of metastatic cells with homeostatic mechanisms which the tumor cells usurp. Most recent data demonstrate that the organ microenvironment can influence the growth, invasion, and response of metastases to chemotherapy. Therapy of metastasis should therefore be targeted against both the metastatic tumor cells and the homeostatic factors that promote metastasis.
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