A Cancer Stem Cell Perspective On Minimal Residual Disease In Solid Malignancies

Minimal residual disease (MRD) is a major difficulty in clinical oncology. It refers to the situation in which seemingly successful therapy is followed by a period of clinical complete remission after which the tumor eventually relapses. This course of events suggests that a small number of tumor cells evaded the therapeutic schedule and give rise to the recurrence, sometimes even after many years. Multiple processes have been advocated to underlie MRD including genetic heterogeneity, cellular dormancy, and also simple stochasticity. In the past decennium, another potential contributing explanation emerged, which is related to the notion that many tumors are hierarchically organized tissues such as advocated by the cancer stem cell model. In particular since it became increasingly clear that cancer stem cells are highly resistant toward chemotherapeutic interventions, this model provides a very elegant framework for MRD. However, the cancer stem cell theory is still an intense field of study, and many challenges remain that each has its own impact on how MRD can be explained as a consequence of therapy-resistant cancer stem cells. This chapter will provide an overview of the developing cancer stem cell model and will outline which important questions remain with respect to the cancer stem cell nature of MRD. In addition we will explore the consequences of drug development of the most recent insights in the cancer stem cell field, such as the central role of the microenvironment and the plasticity of the cancer stem cell population. To conclude we will provide several suggestions as how to optimize clinical evaluation of novel drugs keeping in mind the lessons from the cancer stem cell concept.