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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 of Cancer Growth and Metastasis” supplement reviews fundamental CSC biology, discusses how these cells inform our understanding of mechanisms 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 signaling pathways have been found to be aberrantly operative in CSCs, and may serve as actionable targets to develop CSC-directed therapies. In “Cancer Stem Cell Signaling Pathways,” William H. Matsui, MD, reviews key signaling pathways, such as Wnt, JAK/STAT, and Notch, and provides insight into how the tumor microenvironment supports CSC functions through components of these pathways.
Accumulating evidence supporting the CSC hypothesis in diverse types of cancer is facilitating the development of clinically relevant tumor biology models. In “Cancer Stem Cells: Role in Tumor Growth, Recurrence, Metastasis, and Treatment Resistance,” Jenny C. Chang, MD, highlights the critical role that CSC characteristics, such as stemness, signaling, phenotypic plasticity, and tumor heterogeneity, may play in the disease milestones of tumor growth, treatment resistance, disease recurrence, and metastasis. Dr Chang also discusses the emerging evidence demonstrating the potential of CSC-targeting therapies to be used in combination with conventional treatments to limit tumor growth.
CSC research has greatly contributed to our understanding of cancer pathophysiology and may underpin clinically relevant factors affecting disease outcomes. Yet, significant questions remain regarding CSC biology and the clinical translation of CSC research. In “Cancer Stem Cells: A Nuanced Perspective,” the authors conclude the supplement with insights into the current knowledge gaps regarding the major themes of CSC biology using examples from their own research, discussion of the importance of multidisciplinary approaches to research and therapy development, and recommendations to address limitations and future directions of translating CSC experimental findings to the clinic.
The author reports no conflicts of interest.