Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes?

Evidence is reviewed which suggests a linkage may exist between certain forms of de novo or acquired drug resistance and metastasis. This includes the finding that expression of certain dominantly acting mutant oncogenes or tumor suppressor genes, i.e., genes which normally act to "drive" tumor progression and metastasis, can also affect the expression of drug resistance. Moreover, this can be accompanied by altered expression of certain cellular genes thought to be involved in expression of drug resistance. A direct linkage between acquired drug resistance and metastasis would suggest that tumor sublines selected for drug resistance should manifest more aggressive malignant properties than their drug-sensitive counterparts. While this does not appear to be true for drug resistant sublines selected in vitro, indeed such cell lines frequently manifest diminished in vivo tumorigenic and/or metastatic competence, there is some evidence to support such a correlation exists for tumor cell lines that are selected in vivo for drug resistance. Attention is also drawn to the fact that new linkages between metastasis and drug resistance may be uncovered by analyzing the ability of tumor subpopulations to acquire drug resistance after one or several previous exposures to chemotherapeutic drugs, as opposed to examining intrinsic drug resistance only. Furthermore, ability to detect induced or acquired drug resistance in vitro may be strongly influenced by the types of assay used to detect and monitor drug resistance. In particular, three-dimensional cell culture systems may reveal acquired or induced "multicellular" drug resistance in situations where conventional two-dimensional culture systems do not. Use of three-dimensional culture systems may therefore reveal as yet undiscovered associations between the phenotypes of metastasis and drug resistance.