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ASCO Educational Book; 2009
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The Cancer Stem Cell Hypothesis, Embryonic Signaling Pathways, and Therapeutics: Targeting an Elusive Concept

Lucio Miele, MD, PhD, Naoko Takebe, MD, PhD, and S. Percy Ivy, MD

From the Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL (Dr. Miele), and Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD (Drs. Takebe and Ivy)

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

Address reprint requests to S. Percy Ivy, MD, Associate Chief, Senior Investigator, Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Suite 7131, 6130 Executive Blvd, Rockville, MD; e-mail: ivyp{at}ctep.nci.nih.gov

Overview: The cancer stem cell hypothesis in its simplest form states that solid tumors, like many hematologic malignancies, have a hierarchical cellular organization in which small populations of self-renewing stem-like cells generate the other tumor cells by a process of asymmetric division, proliferation, and abortive differentiation. Scientists continue to debate whether the putative cancer stem cells or tumor-initiating cells (CSCs) derive from the transformation of normal tissue stem cells or from more differentiated cells that reacquire stem-like characteristics as a consequence of transformation. Regardless of the origin of CSCs, the existence of subpopulations of tumor cells with stem-like characteristics, including very slow replication and resistance to standard chemotherapy, poses a therapeutic challenge. If many cancers contain cells that are relatively insensitive to commonly used therapeutics, it is reasonable to hypothesize that these cells may cause disease recurrences and/or metastases after apparently successful treatment. Since disease recurrence after treatment-induced remissions is a major cause of morbidity and mortality, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. Much remains to be clarified about CSCs in individual diseases. However, in many instances, these cells appear to depend on primordial cell fate regulatory pathways that are active during development. Among them, the Notch, Hedgehog, and Wnt pathways play prominent roles, and therapeutic agents that target these pathways are currently in clinical development. This chapter briefly summarizes the current state of development of these investigational agents.