Tumor heterogeneity and its implication for drug delivery.

Evidence continues to accumulate that patient tumors contain heterogeneous cell populations, each of which may contribute differently in extent and mechanism to the progression of malignancy. However, the field of tumor drug delivery research, while continually presenting new and innovative approaches, in many ways continues to operate on the premise that essentially all tumor cells are identical. In some in vivo models, xenograft tumors using cell lines may actually be comparatively homogeneous, and thus result in overly encouraging results when a particular drug or delivery system is reported to successfully treat tumors in mice. It is well known, however, that many drugs that show success in preclinical studies will fail in clinical trials. Tumor heterogeneity is possibly one of the most significant factors that most treatment methods fail to address sufficiently. While a particular drug may exhibit initial success, the eventual relapse of tumor growth is due in many cases to subpopulations of cells that are either not affected by the drug mechanism, possess or acquire a greater drug resistance, or have a localized condition in their microenvironment that enables them to evade or withstand the drug. These various subpopulations may include cancer stem cells, mutated clonal variants, and tumor-associated stromal cells, as well as cells experiencing a spatially different condition such as hypoxia within a diffusion-limited tumor region. This review briefly discusses some of the many aspects of tumor heterogeneity and their potential implications for future drug design and delivery methods.