Cancer Stem Cells

Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance

Huiping Liu, Justin Durla Lathia

• Publisher: Academic Press
• Year: 2016
• Print ISBN:
  9780128038925
• eBook ISBN:
  9780128039342
• Topic: Biological Sciences
• Subtopic: Oncology
• Index: Biological Sciences

Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance introduces the basic concepts and advanced understanding of cancer stem cells, covering general overviews, organ-specific identifications, and their characteristic mechanisms. The book also explores innovative therapeutic strategies in preclinical and clinical trials to target cancer stem cells, remove the roots of cancer, eliminate the seeds of metastasis, overcome the resistance of therapies, and contribute to the eradication of cancer. The book includes contributions from leading, worldwide experts in the field, helping readers embrace new hope in their quest to eradicate cancer with emerging clinical trials on treating cancer stem cells in combination with other therapies. - Provides an authoritative and complete overview of cancer stem cells - Includes comprehensive coverage of current therapeutic strategies targeting cancer stem cells - Deepens a reader's technical expertise in cancer stem cell biology

Section 1

CSC Overview and Methodology

Outline

Chapter 1. Introduction: Cancer Stem Cells

Chapter 2. Overview: Cancer Stem Cell Self-Renewal

Chapter 3. Enrichment and Interrogation of Cancer Stem Cells

Chapter 1

Introduction

Cancer Stem Cells

S.S. Mitra, J.Q. He, R. Esparza, G. Hutter, S.H. Cheshier, and I. Weissman Stanford University, Stanford, CA, United States

Abstract

Cancer stem cells (CSCs) are tumorigenic cells that have the capacity to self-renew and differentiate into various types of cancer cells. It is hypothesized that the stemness of CSCs along with their ability to remain quiescent during periods of intense stress and to be shielded and nourished by their respective niches, allow these cells to evade chemotherapy and radiotherapy, thus making them the prime culprits for cancer recurrence even after aggressive treatment. In recent years, a multitude of models have been developed to study CSC development and propagation. These studies have suggested that successful cancer remission is contingent on the elimination of the CSC population, a task which currently is thought to require multiple synchronized therapies against the various tools these cells have developed to evade eradication. In this chapter, we will begin by characterizing CSCs and conclude with an overview of current therapeutic strategies to target this elusive and lethal cell population.

Keywords

Cancer recurrence; Cancer stem cells (CSC); CD133⁺; CD44⁺; Genetically engineered mouse models; Immunotherapy; Minimal residual disease; Stem cell niche

Contents

Introduction

Cancer Stem Cell Origins

Cancer Stem Cell Generation From a Single Cell of Origin

Two Models for Tumor Growth and Expansion

Identification of the Cancer Stem Cell Population

Features of Cancer Stem Cell

Biomarkers for Cancer Stem Cell Identification

Key Signaling Pathways Involved in Cancer Stem Cell Maintenance

Mouse Models of Cancer Stem Cell Function

Patient-Derived Xenograft Models

Germline Genetically Engineered Mouse Models

Somatic Genetically Engineered Mouse Models

Germline-Derived Allograft Models

Humanized Mouse Models

Strategies for Targeting Cancer Stem Cell

Protective Signaling Pathways

Immunotherapies Against Cell Surface Markers

Tumor Microenvironment—The Complicit Cells of the Cancer Stem Cell Niche

ATP-Binding Cassette Transporters: Multidrug and Redox Stress Resistance

Future of Cancer Stem Cell-Directed Therapies

Conclusion

List of Acronyms and Abbreviations

References

Introduction

Somatic stem cells have been known to exist since at least the 19th century through the study of lower organisms such as planarians and salamanders those were capable of remarkable tissue regeneration [1]. The subsequent study of human teratomas, germ cell tumors that could grow tissues such as bone and teeth in ectopic locations, brought the concept of stem cells—a population of cells which could remain poised and uncommitted to specific lineages even after adulthood—to human biology [2]. By the late 1950s, Conrad Waddington [3] had postulated that by regulating gene expression, cells become more specialized the more they divide—eventually becoming committed to a specific cell fate [3]. The earliest cells in the division hierarchy, termed stem cells, have the capacity not only to divide and proliferate into committed cells, but also to self-renew and create more cells with the same uncommitted identity. These asymmetric divisions thus result in the maintenance of a self-renewing pool of stem cells with a life-long responsibility to provide differentiated cell types. Of note, at each subsequent differentiation step in the cell division hierarchy, self-renewal potential is lost. Committed cells lose their ability to regenerate and therefore generally have limited cellular life spans.

Cancer stem cells (CSCs) are a subset of tumor cells which have escaped cell cycle regulatory mechanisms, cell death, and yet have retained the immense self-renewing and proliferative potential of stem cells [4]. In this manner, they have the capacity to regenerate entire tumors from a limited number of cells. Their existence was first documented by Bonnet and Dick [5] in transplantation studies of human acute myeloid leukemia (AML) in mice with severe combined immunodeficiency disease (SCID). Of the transplanted leukemic cells, only an estimated population of between 0.01 and 1% of the total cell population was capable of initiating AML in the immunocompromised mice. Termed SCID leukemia–initiating cells, they were found to undergo rapid clonal expansion and appeared to be at the top of a cancer cell hierarchy. Later, it was shown that most AML tumor-initiating cells were at the stage of the multipotent progenitors (MPPs), and not the hematopoietic stem cells (HSCs) [6], opening the question as to how does a normally non-self-renewing cells gain both self-renewal and unlimited expansion. The introduction of the CSC hypothesis has led to new developments and insights into the nature of tumor propagation and possible therapeutic targets. Yet, much is still unknown about this important tumor cell subtype in each of the human and experimental cancers. In this chapter, we will discuss the biological properties of CSCs, current research on their identification and function, and future goals for CSC-directed therapies.

Cancer Stem Cell Origins

Cancer Stem Cell Generation From a Single Cell of Origin

The cells within a tumor are derived from tissues and organs which contain normal stem cells, progenitors, and lineage committed cells, eg, the lineage hierarchy of the blood system. Identifying the complete roadmap of transitions from HSC through MPPs lacking self-renewal (short term-HSC, MPPs [7,8]) to common myeloid progenitor in mice [9] and humans [10], and Common lymphoid progenitor (CLP) [11], and downstream from them ever more committed progenitors (eg, granulocyte–macrophage progenitor (GMP) and megakaryocyte/erythroid progenitor) [9,12] allowed Weissman and colleagues to phenotypically isolate the cell types from which gave rise to leukemias. The critical development of a strain of mice where two pathways important in programmed cell death was blocked in hematopoetic cells [13]. Serial transplantation of leukemias from mice that developed AML could only be achieved with GMP cells. They further inferred that the progression to leukemia required at least five to seven rare events, either genetic or epigenetic; however, most of these events could not confer self-renewal, and so must have occurred in self-renewing cells to persist sufficiently to form a clone that was leukemic [14]. The pathways from the cell type that acquired the first oncogenic mutation, also known as the cell of origin to CSC, are varied and complex. However, it has been shown that in in vitro models of hematopoietic malignancy, certain oncoproteins may activate genetic programs involved in self-renewal, thereby conferring “stemness” to committed malignant cells and leading to the creation of CSCs [15–17]. In vivo studies using an MLL1–AF9 mouse model of AML confirmed this finding but with an additional caveat: the amount of translocation product expressed determined the efficiency of CSC generation [18]. Below a certain thres...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Foreword by Jane Visvader
• Foreword by Stanton L. Gerson
• Preface
• Acknowledgments
• Section 1. CSC Overview and Methodology
• Section 2. CSCs in Representative Organ Systems
• Section 3. CSC Features and Mechanisms
• Section 4. Clinical Applications
• Index