Review Cancer Stem Cells Targeting Cancer Stem Cells—A Renewed Therapeutic Paradigm Catherine L Amey 1 and Antoine E Karnoub 2 1. Touch Medical Media, Goring-On-Thames, UK; 2. Department of Pathology, Beth Israel Deaconess Cancer Center and Harvard Medical School, Boston, Massachusetts, US; Harvard Stem Cell Institute, Cambridge, Massachusetts, US; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, US M etastasis is often accompanied by radio- and chemotherapeutic resistance to anticancer treatments and is the major cause of death in cancer patients. Better understanding of how cancer cells circumvent therapeutic insults and how disseminated cancer clones generate life-threatening metastases would therefore be paramount to the development of effective therapeutic approaches for clinical management of malignant disease. Mounting reports over the past two decades have provided evidence for the existence of a minor population of highly malignant cells within liquid and solid tumors, which are capable of self-renewing and of regenerating secondary growths with the heterogeneity of the primary tumors from which they derive. These cells, called tumor-initiating cells or cancer stem cells (CSCs) exhibit increased resistance to standard radio- and chemotherapies and appear to have mechanisms that enable them to evade immune surveillance. CSCs are therefore considered to be responsible for systemic residual disease after cancer therapy, as well as for disease relapse. How CSCs develop, the nature of the interactions they establish with their microenvironment, their phenotypic and functional characteristics, as well as their molecular dependencies have all taken center stage in cancer therapy. Indeed, improved understanding of CSC biology is critical to the development of important CSC-based anti-neoplastic approaches that have the potential to radically improve cancer management. Here, we summarize some of the most pertinent elements regarding CSC development and properties, and highlight some of the clinical modalities in current development as anti-CSC therapeutics. Keywords Cancer biomarker, cancer stem cell, tumor-initiating cell, microenvironment, signaling pathway, targeted therapy, radioresistance, chemoresistance Disclosure: Antoine E Karnoub has nothing to declare in relation to this article. Catherine L Amey is an employee of Touch Medical Media, Goring-On-Thames, UK. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: February 22, 2017 Accepted: April 20, 2017 Citation: Oncology & Hematology Review, 2017;13(1):45–55 Corresponding Author: Antoine E Karnoub, Center for Life Science 0634, 3 Blackfan Circle, Boston, MA 02215, US. E: akarnoub@bidmc.harvard.edu Support: The publication of this article was supported by Boston Biomedical, who was given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion. TOU CH MED ICA L MEDIA Despite substantial advances in cancer diagnosis and treatment, the long-term survival rate for many cancer patients remains dismal. 1 More than 90% of cancer-related mortality is ascribed to disease resurgence months or years after adjuvant therapy, either in the form of local recurrence or in the form of metastatic spread, which are typically refractory to existing treatment modalities (see Table 1). 1,2 Novel anti-neoplastic therapeutic approaches aimed at eradicating residual relapsing disease are therefore sorely needed, but remain to be defined. The cornerstone of current cancer management approaches relies on early detection and on chemotherapeutic and radiologic treatment of diagnosed neoplasms. Although detection methodologies have helped significantly in reducing the lethality associated with cancers such as prostate or breast neoplasms, they have had limited widespread efficacy in many others. Indeed, efforts to diagnose cancers early in their development are still hampered by serious limitations in technologies that cannot detect small tumorigenic growths or disseminated microscopic disease. Similarly, classical anti-neoplastic treatments, which target highly proliferating cancer cells, non- discriminately target bystander normal cells, such as hair follicle cells or gut-regenerating cells, causing high degree of systemic toxicity. In addition, these systemic therapies, are, to a large extent, inefficient in eradicating disseminated disease, and often result in the emergence of resistance. The discovery that unchallenged human primary tumors harbor subpopulations of cancer cells that are distinguished from bulk populations by exclusive abilities to self-renew and generate heterogeneous secondary growths refocused attention on understanding the fundamental biology of how these cells emerge, and on identifying means to kill them. Such tumor-initiating cells (TICs), dubbed cancer stem cells (CSCs), which pre-exist already in untreated tumors, were found to be amplified in recurrent disease, and were shown to be highly malignant and with augmented tolerance to existing radio- and chemotherapeutics. 3 Indeed, it is widely accepted that CSCs represent the root cause for metastatic dissemination and disease relapse in cancer patients. As such, the identification of effective CSC-specific therapeutics has taken center stage in the development of anti-neoplastic therapies aimed at eradicating disease relapse. 4 45