Cancer stem cells: master gatekeepers and regulators of cancer growth and metastasis Introduction

Although cancer treatment has progressed significantly since the emergence of scientific oncology in the early 19th century, the disease remains incurable. Almost all deaths among cancer patients are attributed to treatment resistance, relapse, and metastasis. Yet, the mechanisms of resistance and disease spread are unclear.Mounting experimental and clinical evidence suggests that the stem cell-like properties of a subpopulation of tumorigenic cancer cells, known as cancer stem cells (CSCs), may underlie a broad spectrum of cancer pathophysiology, including cancer initiation, growth, treatment resistance, disease recurrence, and metastasis. This “Cancer Stem Cells: Master Gatekeepers and Regulators ofCancerGrowthandMetastasis” supplement reviews fundamental CSC biology, discusses how these cells inform our understanding ofmechanisms governing key tumor functions, and provides insight from key opinion leaders regarding the challenges and future directions of CSC research. Cancer prognosis and treatment efficacy may be limited by molecular and cellular heterogeneity between and within individual tumors. How such differences develop from disease inception through metastasis in various types of cancer remains uncertain. In “Cancer Stem Cells: Understanding Tumor Hierarchy and Heterogeneity,” I provide historical highlights of the CSC hypothesis, key functional stemness properties of CSCs, and comparisons and contrasts of such functions with those of normal stem cells as context to outline the role of CSCs in models of cancer cell hierarchies that may account for tumor heterogeneity. Studies suggest that dysregulation of normal homeostatic and developmental signaling pathways drive the hallmarks of CSCs, such as self-renewal and differentiation into heterogeneous cancer cell populations. Unsurprisingly, several normal stem cell