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Review
. 2015 Oct;27(5):437-49.
doi: 10.3978/j.issn.1000-9604.2015.04.08.

Circulating cancer stem cells: the importance to select

Ming-Hsin Yang  1 , Ahmet Imrali  1 , Christopher Heeschen  1
Affiliations
Review

Circulating cancer stem cells: the importance to select

Ming-Hsin Yang et al. Chin J Cancer Res. 2015 Oct.

Abstract

It has been demonstrated that even localized tumors without clinically apparent metastasis give rise to circulating tumor cells (CTCs). A growing number of technically diverse platforms are being developed for detecting/isolating CTCs in the circulating blood. Despite the technical challenges of isolating rare CTCs from blood, recent studies have already shown the predictive value of CTCs enumeration. Thus, it is becoming increasingly accepted that CTC numbers are linked to patients' outcome and may also be used to monitor treatment response and disease relapse, respectively. Further CTCs provide a non-invasive source for tumor material, 'liquid biopsy', which is particularly important for patients, where no biopsy material can be obtained or where serial biopsies of the tumor, e.g., following treatment, are practically impossible. On the other hand the molecular and biological characterization of CTCs has still remained at a rather experimental stage. Future studies are necessary to define CTC heterogeneity to establish the crucial role of circulating cancer stem cells for driving metastasis, which represent a distinct subpopulation of CTCs that bear metastasis-initiating capabilities based on their stemness properties and invasiveness and thus are critical for the patients' clinical outcome. As compared to non-tumorigenic/metastatic bulk CTCs, circulating cancer stem cells may not only be capable of evading from the primary tumor, but also escape from immune surveillance, survive in the circulating blood and subsequently form metastases in distant organs. Thus, circulating cancer stem cells represent a subset of exclusively tumorigenic cancer stem cells characterized by their invasive characteristics and are potential therapeutic targets for preventing disease progression. To date, only a few original reports and reviews have been published focusing on circulating cancer stem cells. This review discusses the potential importance of isolating and characterizing these circulating cancer stem cells, but also highlights current technological limitations.

Keywords: Cancer stem cells; circulating tumor cells (CTCs); drug resistance.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The metastatic process. The complex process of metastasis includes induction of EMT, detachment, invasion of the tumor microenvironment and shedding of CTCs into the blood stream (intravasation). Apparently, the majority of CTCs relate to differentiated cancer cells that do not bear tumorigenicity and are rather prone to undergo anoikis. However, CTCs that bear cancer stem cell features, i.e., circulating cancer stem cells, are able to survive in the circulating blood, escape from immune surveillance, home to secondary sites, extravasate, undergo MET, and thus may eventually form distant metastatic lesions. EMT, epithelial-to-mesenchymal transition; CTCs, circulating tumor cells; MET, mesenchymal-epithelial transition.
Figure 2
Figure 2
The hierarchical organization of cancer and metastasis. Cancer stem cells are capable of undergoing unlimited cell division while retaining their stem cell identity (self-renewal) and giving rise to progenies with limited proliferative capacity (differentiation). Cancer stem cells evolve during tumor progression by acquiring further genetic or epigenetic changes, but may also advance through interactions with the tumor microenvironment. Both cancer stem cells and non-cancer stem cells may be found at the invasive front of primary tumors with similar invasive/migratory features, a process frequently linked to the process of EMT. However, only cells with cancer stem cell features will be able to give rise to metastasis. Such circulating cancer stem cells may arise via two non-exclusive mechanisms: (I) circulating cancer stem cells may already exist in the primary tumor as cancer stem cells with additional features rendering them capable of surviving in the blood stream and subsequently initiating metastatic spread; (II) disseminated tumor cells, after a varying period of dormancy, may convert into circulating cancer stem cells through processes that are yet to be elucidated. Such circulating cancer stem cells derived from disseminated (originally non-metastatic) tumor cells must have acquired additional features in order to not only survive the hostile environment of the blood stream, evade immune surveillance, and extravasate at a distant location, but to also be able to form secondary lesions (tumorigenicity). Of note, circulating cancer stem cells may also originate from metastatic lesions and subsequently recolonize the tumor of origin, a process called “tumor reseeding”.
Figure 3
Figure 3
Circulating tumor cells (CTCs) as a tool for basic and clinical research platforms. The proposed model for CTC/cancer stem cell workflows starts with the isolation of high purity tumor cells from the blood, for which a number of different platforms can be used. For exploratory research, the isolated cells can then be expanded in vitro or in vivo to generate CTC-derived xenografts (CDX). These models are used for molecular characterization of circulating cancer stem cells and and differentiated progenies as well as generating drug response profiles. These diverse data sets should be merged and processed by bioinformatic analysis in order to generate new hypotheses that are subsequently tested in preclinical studies using above model systems. On the other hand, isolated CTCs/cancer stem cells may also be used directly in a translational manner allowing us to identify therapeutic targets based on molecular analysis of the cells, hence achieving the prospect of tailored treatment strategies for individual patients. Such innovative precision medicine strategies must then be tested and validated in prospective clinical trials.
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