Cancer stem cells: implications for the progression and treatment of metastatic disease

Abstract

Metastasis is the major cause of death for cancer patients with solid tumours, due mainly to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of metastasis is therefore essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies. Metastasis is an inefficient process, such that very few cells that leave a tumour successfully form macrometastases in distant sites. This suggests that only a small subset of cells can successfully navigate the metastatic cascade and eventually re-initiate tumour growth to form life-threatening metastases. Recently, there has been growing support for the cancer stem cell (CSC) hypothesis which stipulates that primary tumours are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. Classical properties of normal stem cells are strikingly reminiscent of the observed experimental and clinical behaviour of metastatic cancer cells, including an unlimited capacity for self renewal; the requirement for a specific 'niche' or microenvironment to grow; use of the stromal cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) axis for migration; enhanced resistance to apoptosis and an increased capacity for drug resistance. Therefore, in addition to playing a role in primary tumour formation, we believe that CSCs are also key players in the metastatic process. We will review the current evidence supporting this idea and discuss the potential implications of the CSC hypothesis with regards to experimental investigation and treatment of metastatic disease.

1

The successful metastatic cell must carry out a number of sequential steps in order to form clinically relevant metastases. Based on the complexity of the metastatic process, it seems unlikely that all cancer cells would be able to successfully complete all the steps necessary to form macrometastases. Indeed, it is known that metastasis is a highly inefficient process, and that not all the steps of the metastatic process are equally inefficient. The principal rate limiting steps are (5) initiation of growth into micrometastases; and (6) maintenance of growth into macrometastases, whereby less than ∼2% of solitary cells are able to initiate growth and less than ∼0.02% of cells are able to maintain growth into clinically relevant metastases [10, 12, 13].