Targeting a cornerstone of radiation resistance: Cancer stem cell

Abstract

In radiation oncology, cancer stem cells (CSCs) have become an important research field. In fact, it appears that most cancer types contain populations of cells that exhibit stem-cell properties. CSCs have the ability to renew indefinitely, which can drive tumor development and metastatic invasion. As those cells are classically resistant to conventional chemotherapy and to radiation therapy, they may contribute to treatment failure and relapse. Over past decades, preclinical research has highlighted that variations in the CSCs content within tumor could affect their radiocurability by interfering with mechanisms of DNA repair, redistribution in the cell cycle, tumor cells repopulation, and hypoxia. It is now possible to isolate particular cells expressing specific surface markers and thus better investigating CSCs pathways. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials. By targeting CSCs, tumor radioresistance could be potentially overcome to improve outcome for patients with solid malignancies. Radiation therapy using ion particles (proton and carbon) may be also more effective than classic photon on CSCs. This review presents the major pathophysiological mechanisms involved in CSCs radioresistance and recent developments for targeted strategies.

Introduction

For over a half a century, cancer stem cells (CSCs) have been an important area of radiation research. It appears that most cancers contain populations of cells that exhibit stem-cell properties. Those are characterized by their ability to self-renew and may produce a much larger set of cells with very limited proliferative potential that are named the bulk. The definition of a CSC requires three characteristics: (i) a selective capacity to initiate tumor and drive neoplastic proliferation, (ii) an ability to generate endless copies of themselves through self-renewal, and (iii) the potential to give rise to more differentiated non-stem cell cancer progeny [1].

Since CSCs have been described for first time in leukaemia by the Dick laboratory in 1994, other groups have demonstrated the presence of CSCs in numerous solid tumors (glioblastoma, colorectal cancer, prostate, head and neck, liver, melanoma, etc.), suggesting that the majority of malignancies are dependent on such a cell compartment. Anyhow, properties of CSCs in different tumors were not similar, and the proportion of stem cells in tumors was different [2]. Moreover, the origin of CSCs remains unclear and many works tried to identify this. Barker et al. [3], Zhu et al. [4], and Alcantara Llaguno et al. [5] demonstrated that CSCs were derived from normal stem cells if oncogenes were activated. But, there is evidence that more differentiated cancer cell populations may acquire CSC properties through epithelial mesenchymal transition (EMT) [6], [7]. Chaffer et al. [8] recently observed in a subpopulation of basal-like human mammary epithelial cells that spontaneously dedifferentiated into stem-like cells. Then, some non-stem cancer cells gave rise to CSCs. Classically, the definition of adult stem cell implicates that those are capable to generate full cellular components of the relevant organ from a single stem cell. This could be revealed by in vivo functional assays, which consists in implanting a progressively smaller number of tumor cells in immunodeficient animals. The number of cells could be an appropriate surrogate when analyzing the frequency of proper cancer stem cells. Now, through the development of immunofluorescence tools, it is possible to more easily isolate CSCs using their surface proteins (e.g. CD133, CD44, CD29).

Cancer stem cells account for a minor fraction of a tumor population, but those might be particularly involved in tumor initiation, proliferation, or in metastatic process. CSCs are believed to share many properties with normal stem cells that render them relatively insensitive to conventional cytotoxic agents, such as chemotherapy and to radiation therapy. This is an advocated factor of treatment failure and relapse. The mechanisms through which solid tumors become resistant to conventional therapy are only partially understood. Those involve numerous factors implicated in the resistance of CSC to ionizing radiation: quiescence propensity, enhanced DNA repair, upregulated cell cycle control mechanisms, mechanisms of free-radical scavenging, and specific interaction with stromal microenvironnement [9], [10]. From a radiobiological point of view, four factors are classically involved in the efficiency of ionizing radiation: repair of DNA damage systems, redistribution of the cell cycle, tumor cells repopulation, and level of intratumor hypoxia. Although the identity of cancer cell clonogens has not been definitively resolved, the understanding of CSCs pathways continues to grow and new potential molecular therapeutic targets have recently emerged. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials (http://clinicaltrials.gov: NCT01122901, NCT01351103). Overcoming radioresistance by concurrently targeting cancer stem cells pathways may potentially improve outcome for patients with localized solid tumors. Radiation therapy using heavy particles (proton and carbon) may be also more effective than classic photon on CSCs [11], [12]. The aim of this paper is to report the various intracellular pathways involved in CSCs radioresistance for which potential intracellular target and highlight strategies for enhancing antitumor effectiveness.