Cancer stem cells and their role in metastasis

Abstract

Cancer stem cells (CSCs), which comprise a small fraction of cancer cells, are believed to constitute the origin of most human tumors. Considerable effort has been focused on identifying CSCs in multiple tumor types and identifying genetic signatures that distinguish CSCs from normal tissue stem cells. Many studies also suggest that CSCs serve as the basis of metastases. Yet, experimental evidence that CSCs are the basis of disseminated metastases has lagged behind the conceptual construct of CSCs. Recent work, however, has demonstrated that CSCs may directly or indirectly contribute to the generation of metastasis. Moreover, CSC heterogeneity may be largely responsible for the considerable complexity and organ specificity of metastases. In this review, we discuss the role of CSCs in metastasis and their potential as therapeutic targets.

Fig 1. Multiple hypotheses examining the origin of CSCs and metastases

A. Only the CSCs in primary tumors can home and metastasize to distant tissues directly. B. CSCs are generated in primary tumors that ultimately undergo an EMT to generate CTCs. The CTCs home to distant tissues and undergo mesenchymal to epithelial transition establishing the disseminated CSCs. C. In some specific tumor types, all the cancer cells including CSCs demonstrate no significant differences in the ability to generate tumors or establish metastases distant sites in animal models. D. Non-stem-like cancer cells shed as CTCs from primary tumors circulate and home to distant tissues. Once in the distant site, the cancer cells became CSCs through de-differentiation.

Fig 2. Competition and engagement of the HSC niche and its role in CSC maintenance and dormancy

A. CSCs compete with HSCs for engagement of the osteoblastic HSC niche which regulates quiescence and proliferation of HSCs. HSCs which are displaced from the niche are found in the peripheral circulation. B. PCa cells which enter the niche as either CSCs are or more mature cells are “dedifferentiated”into CSCs and or maintained as stem cells. C. Once in the HSC niche, CSCs may undergo either growth arrest or exit the cell cycle in G₀ and become dormant D. After asymmetric cell division, progeny of CSCs may either return to the niche as a CSCs or may terminally differentiate following additional proliferative activities which result in the establishment of metastatic bone lesions.

Fig 3. Potential therapeutic strategies to specifically target metastatic CSCs

E. CSCs are eradicated with compounds that selectively target the CSC phenotype. F. CSCs spontaneously undergo apoptosis when the nutritional support from the surrounding vasculature is withdrawn. G. CSCs can be terminally differentiated to avoid proliferation and dedifferentiation. H. Once CSCs reside within the niche, they are thought to become dormant. If CSCs are displaced from the niche, they are activated and therefore become susceptible to cytotoxic treatment.