The developing cancer stem-cell model: clinical challenges and opportunities

Summary

During the past decade, a stem-cell-like subset of cancer cells has been identified in many malignancies. These cells, referred to as cancer stem cells (CSCs), are of particular interest because they are believed to be the clonogenic core of the tumour and therefore represent the cell population that drives growth and progression. Many efforts have been made to design therapies that specifically target the CSC population, since this was predicted to be the crucial population to eliminate. However, recent insights have complicated the initial elegant model, by showing a dominant role for the tumour microenvironment in determining CSC characteristics within a malignancy. This is particularly important since dedifferentiation of non-tumorigenic tumour cells towards CSCs can occur, and therefore the CSC population in a neoplasm is expected to vary over time. Moreover, evidence suggests that not all tumours are driven by rare CSCs, but might instead contain a large population of tumorigenic cells. Even though these results suggest that specific targeting of the CSC population might not be a useful therapeutic strategy, research into the hierarchical cellular organisation of malignancies has provided many important new insights in the biology of tumours. In this Personal View, we highlight how the CSC concept is developing and influences our thinking on future treatment for solid tumours, and recommend ways to design clinical trials to assess drugs that target malignant disease in a rational fashion.

Introduction

In recent years, the cancer stem-cell (CSC) theory of malignancies has received much attention. Although the idea that malignancies depend on a small population of stem-like cells for proliferation has been around for more than a century, technical developments only in the past few decades made it possible to strengthen these speculations with experimental data.¹ An important reason for the widespread interest in the CSC model is that it can comprehensibly explain essential, poorly understood clinical events, such as therapy resistance, minimal residual disease, and tumour recurrence. In many cases, however, the initial explanatory power of the CSC model has waned as novel data challenge and redefine the CSC concept. The original, somewhat rigid interpretation of the model presents malignancy as a hierarchically organised tissue with a CSC population at the top that generates the more differentiated bulk of the tumour cells (figure 1A).² In this model, the differentiated tumour cells have lost their clonogenic capacity and only the CSCs contribute to the expansion and long-term progression of the malignancy. This model suggests that CSCs should be the target for successful therapeutic intervention. Unfortunately, CSCs seem to be more resistant than differentiated tumour cells to most of the common therapies,3, 4, 5, 6, 7, 8 which could explain therapeutic failure; the applied drug effectively kills most of the differentiated tumour cells, resulting in tumour shrinkage, yet the CSCs are relatively unharmed and reside in the fibrotic tissue that remains from the initial tumour bulk. After therapy is discontinued, the highly tumorigenic CSCs resume growth, which clinically manifests itself as a relapse. With this in mind, many researchers were convinced that specific and effective targeting of the CSC population could cure the patient. Crucially, this assumption relies on the idea that the CSC population is stable over time, and that CSC features are intrinsic qualities that cannot be attained by differentiated tumour cells. However, novel data, from our group and several others, suggest that this is not the case.9, 10, 11, 12 The CSC phenotype is much more fluid than anticipated and is strongly regulated by the tumour-cell environment. We refer to this concept as the dynamic CSC model (figure 1B); this nuanced view of the nature of CSCs might settle much of the dispute between those who view CSCs as a factual entity and those who consider them an illusion. Additionally, this notion directly affects the design of novel therapies aimed at targeting the CSC population. In any case, research into the CSC concept has substantially expanded our knowledge of the biology of malignancies, including response to therapeutic interventions. These insights will have an effect on clinical oncology in the near future. In this Personal View, we highlight the latest developments in CSC research and discuss the implications for clinical oncology; these mainly relate to identification of novel targets to overcome therapy resistance, and improved setups for clinical trials that take into account the efficacy of interventions on the CSC compartment.