Tackling the cancer stem cells - what challenges do they pose?

Abstract

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.

Figure 1

Why specific targeting of CSCs is important. (A) Why specific targeting of CSCs is important: Two major issues confound our ability to treat cancers – their ability to resist cytotoxic therapy and their propensity to form metastases. Tumors are a heterogeneous mixtures of epithelial cells that consist of CSCs that have mixed epithelial-mesenchymal phenotypes and non-stem cells which are epithelial. Carcinoma cells may also be able to undergo a complete EMT, generating cells that resemble stromal-like fibroblasts and mesenchymal stem cells that may create a permissive niche. (B) The use of specific inhibitors of CSCs would attenuate their ability to survive conventional cytotoxic therapies and relapse. Loss of the mesenchymal/CSC population would also retard metastatic spread of the tumor.

Figure 1

Why specific targeting of CSCs is important. (A) Why specific targeting of CSCs is important: Two major issues confound our ability to treat cancers – their ability to resist cytotoxic therapy and their propensity to form metastases. Tumors are a heterogeneous mixtures of epithelial cells that consist of CSCs that have mixed epithelial-mesenchymal phenotypes and non-stem cells which are epithelial. Carcinoma cells may also be able to undergo a complete EMT, generating cells that resemble stromal-like fibroblasts and mesenchymal stem cells that may create a permissive niche. (B) The use of specific inhibitors of CSCs would attenuate their ability to survive conventional cytotoxic therapies and relapse. Loss of the mesenchymal/CSC population would also retard metastatic spread of the tumor.

Figure 2

Signaling pathways employed by CSCs: Distinct combinations of paracrine and juxtracrine signals induce the EMT in different contexts. A representation of signaling pathways that CSCs have been reported to depend on is shown here. The transcription factors that are downstream of these signaling pathways act as co-factors and cooperate with the EMT-inducing transcription factors such as Snail to induce and maintain the mesenchymal/CSC state. The EMT program also activate several positive, self-reinforcing feedback loops in order to maintain cells in a mesenchymal/CSC state; shown here are three involving canonical and non-canonical Wnts as well as TGF-β. Nodes of the pathway that could be open to therapeutic targeting are indicated by red arrowheads.

Figure 3

Impact of stromal cells and secreted factors on CSCs – Each stromal cell type depicted here influences the tumor by secreting factors that stimulate the formation of CSCs and help maintain the residence of already-formed CSCs in the SC state. Summarized here are some of the major factors that secreted by each cell type that are known to impact CSCs. Green arrow – Tumor promotion, Red crossbar – Tumor inhibition.

Figure

Illustration of tumor microenvironment showing all major constituents mentioned above