[Frontiers in Bioscience 16, 368-392, January 1, 2011]

[Frontiers in Bioscience 16, 368-392, January 1, 2011]

Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer

Michael D. Curley¹, Leslie A. Garrett^1,2,3, John O. Schorge^2,3, Rosemary Foster^1,3, Bo R. Rueda^1,2,3

1Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; ²Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; ³Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02114, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Cancer stem cell hypothesis
4. Key characteristics of cancer stem cells
5. Origin of cancer stem cells
6. Evidence of cancer stem cells in human cancers
7. Ovarian cancer stem cells: 7.1. Side population (SP); 7.2. CD44; 7.3. CD117/c-KIT; 7.4. MyD88; 7.5. CD133
8. Current methodologies for human ovarian tumor cell propagation
9. Use of established human ovarian cancer cell lines
10. In vitro propagation of primary ovarian tumor cells as non-adherent spheroids
11. In vivo propagation of primary human tumors in xenograft mouse models
12. Additional caveats of the xenograft model: 12.1. Solid tumors; 12.2. Site of injection; 12.3. Human versus mouse microenvironments; 12.4. Mouse strain used
13. Clinical strategies aimed at cancer stem cells 13.1. Direct targeting of cancer stem cells 13.1.1. Hedgehog signaling pathway 13.1.2. Notch signaling pathway 13.1.3. Wnt signaling pathway 13.1.4. Additional targets for therapy: 13.2. Induction of cancer stem cell differentiation/proliferation; 13.3. Destruction of the cancer stem cell niche/stromal supportive environment
14. Perspective
15. Acknowledgements

1. ABSTRACT

Ovarian cancer represents the most lethal gynecologic malignancy, primarily due to a lack of early detection, which results in most patients being diagnosed at an advanced stage of disease. Though the ovarian surface epithelium is thought to provide the primary site of tumorigenesis, the exact etiology of the various tumor types associated with this disease remain undefined. Recent evidence suggests that ovarian tumors, like other solid tumors, contain distinct populations of cells that are responsible for tumor initiation, maintenance and growth. These specialized cells, termed cancer stem cells, display some of the hallmarks of normal stem cells and are thought to evade current chemotherapeutic strategies, resulting in an increased risk of recurrence. Here we review evidence for the existence of cancer stem cells in ovarian malignancies and their contribution to the pathology of this disease, critically evaluate the methods used for ovarian cancer stem cell definition and isolation, and discuss their clinical relevance.