Tumour-initiating cells: challenges and opportunities for anticancer drug discovery

Abstract

The experimental demonstration of tumour-initiating cells (popularly known as cancer stem cells) in several human tumours in recent years supports tumour hierarchy as a fundamental concept in tumour biology. Many patients with cancer, particularly those with solid tumours, either do not respond to existing cancer therapies or relapse quickly after initial remission. Key possible reasons for this failure include the inherent drug resistance of tumour-initiating cells, the inefficiency of the treatment and/or the genetic instability of cancer cells. The cancer stem cell hypothesis provides a rationale for several therapeutic strategies beyond traditional antiproliferative agents. Potential approaches to kill tumour-initiating cells include inhibiting the survival mechanisms of these cells, blocking essential self-renewal signalling, or targeting tumour-initiating cell surface markers through antibody-based cytotoxic approaches. Another strategy is to induce tumour cell differentiation, which can potentially be achieved by inhibiting developmental pathways or epigenetic programmes. As many tumour-initiating cells might be dependent on a niche for their identities, targeting the niche could be a strategy to indirectly inhibit or differentiate tumour-initiating cells. The conventional approach for anticancer drug discovery is to target cell proliferation rather than self-renewal and/or differentiation, and so is often biased to select targets with homogeneous expression patterns and potent compounds that kill the cells of the bulk tumour. In addition, some traditional preclinical models may not reflect clinical complexities such as tumour hierarchy. The large body of evidence in support of the cancer stem cell hypothesis and the related therapeutic strategies suggest that adjustments to anticancer drug discovery platforms are required to make them more clinically relevant, which are discussed in this article. Although the paths for developing agents that target tumour-initiating cells are not straightforward, the cancer stem cell hypothesis provides an important framework for drug discovery and cancer treatment, with the potential to find novel antitumour activities, to have an impact on cancers with undifferentiated phenotypes and to yield long-term benefits for many patients with cancer.