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.