Cells of origin in cancer VISVADER, Jane E
Nature (London),
01/2011, Letnik:
469, Številka:
7330
Journal Article
Recenzirano
Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but ...evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer.
The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem ...and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarchy. Potential relationships between normal epithelial populations and breast tumor subtypes are discussed, with implications for understanding the cellular etiology underpinning breast tumor heterogeneity.
The mammary epithelium is highly responsive to local and systemic signals, which orchestrate morphogenesis of the ductal tree during puberty and pregnancy. Based on transplantation and lineage ...tracing studies, a hierarchy of stem and progenitor cells has been shown to exist among the mammary epithelium. Lineage tracing has highlighted the existence of bipotent mammary stem cells (MaSCs) in situ as well as long-lived unipotent cells that drive morphogenesis and homeostasis of the ductal tree. Moreover, there is accumulating evidence for a heterogeneous MaSC compartment comprising fetal MaSCs, slow-cycling cells, and both long-term and short-term repopulating cells. In parallel, diverse luminal progenitor subtypes have been identified in mouse and human mammary tissue. Elucidation of the normal cellular hierarchy is an important step toward understanding the "cells of origin" and molecular perturbations that drive breast cancer.
Breast cancer remains a leading cause of cancer-related mortality in women, reflecting profound disease heterogeneity, metastasis, and therapeutic resistance. Over the last decade, genomic and ...transcriptomic data have been integrated on an unprecedented scale and revealed distinct cancer subtypes, critical molecular drivers, clonal evolutionary trajectories, and prognostic signatures. Furthermore, multi-dimensional integration of high-resolution single-cell and spatial technologies has highlighted the importance of the entire breast cancer ecosystem and the presence of distinct cellular “neighborhoods.” Clinically, a plethora of new targeted therapies has emerged, now being rapidly incorporated into routine care. Resistance to therapy, however, remains a crucial challenge for the field.
Breast cancer is a complex and heterogeneous disease that is a leading cause of mortality in women. Understanding the disease subtypes, drivers, evolution, microenvironment, and resistance to therapy is providing new directions for the field and for patient care.
The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor ...cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.
Recent work in the field of stem cell biology suggests that there is no single design for an adult tissue stem cell hierarchy, and that different tissues employ distinct strategies to meet their ...self-renewal and repair requirements. Stem cells may be multipotent or unipotent, and can exist in quiescent or actively dividing states. 'Professional' stem cells may also co-exist with facultative stem cells, which are more specialized daughter cells that revert to a stem cell state under specific tissue damage conditions. Here, we discuss stem cell strategies as seen in three solid mammalian tissues: the intestine, mammary gland and skeletal muscle.
The cancer stem cell (CSC) model has been established as a cellular mechanism that contributes to phenotypic and functional heterogeneity in diverse cancer types. Recent observations, however, have ...highlighted many complexities and challenges: the CSC phenotype can vary substantially between patients, tumors may harbor multiple phenotypically or genetically distinct CSCs, metastatic CSCs can evolve from primary CSCs, and tumor cells may undergo reversible phenotypic changes. Although the CSC concept will have clinical relevance in specific cases, accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumor to prevent relapse.
The mammary epithelium undergoes profound morphogenetic changes during development. Architecturally, it comprises two primary lineages, the inner luminal and outer myoepithelial cell layers. Two ...opposing concepts on the nature of mammary stem cells (MaSCs) in the postnatal gland have emerged. One model, based on classical transplantation assays, postulates that bipotent MaSCs have a key role in coordinating ductal epithelial expansion and maintenance in the adult gland, whereas the second model proposes that only unipotent MaSCs identified by lineage tracing contribute to these processes. Through clonal cell-fate mapping studies using a stochastic multicolour cre reporter combined with a new three-dimensional imaging strategy, we provide evidence for the existence of bipotent MaSCs as well as distinct long-lived progenitor cells. The cellular dynamics at different developmental stages support a model in which both stem and progenitor cells drive morphogenesis during puberty, whereas bipotent MaSCs coordinate ductal homeostasis and remodelling of the mouse adult gland.
Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic ...refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.
To examine global changes in breast heterogeneity across different states, we determined the single‐cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1+/– tissue, ...the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post‐menopausal women. Single‐cell profiling of 34 treatment‐naive primary tumors, including estrogen receptor (ER)+, HER2+, and triple‐negative breast cancers, revealed comparable diversity among cancer cells and a discrete subset of cycling cells. The transcriptomes of preneoplastic BRCA1+/– tissue versus tumors highlighted global changes in the immune microenvironment. Within the tumor immune landscape, proliferative CD8+ T cells characterized triple‐negative and HER2+ cancers but not ER+ tumors, while all subtypes comprised cycling tumor‐associated macrophages, thus invoking potentially different immunotherapy targets. Copy number analysis of paired ER+ tumors and lymph nodes indicated seeding by genetically distinct clones or mass migration of primary tumor cells into axillary lymph nodes. This large‐scale integration of patient samples provides a high‐resolution map of cell diversity in normal and cancerous human breast.
Synopsis
To examine global changes in breast heterogeneity across different states, this gene expression resource integrates large‐scale patient samples from diverse tissue states and breast cancer subtypes, offering a refined high‐resolution map of cell diversity in the normal and cancerous human mammary gland.
Single‐cell transcriptome analyses profile > 340,000 cells encompassing normal breast, preneoplastic BRCA1+/– tissue, the major breast cancer subtypes, and metastatic lymph nodes.
Pre‐ to post‐menopause transition is associated with marked stromal changes, with decreased PDGFRb and matrix‐associated genes in fibroblasts.
Progression from preneoplasia to tumors correlates with increased immune infiltration in BRCA1 mutation carriers.
Tumor epithelial compartments show comparable diversity in different breast cancer subtypes.
Cycling CD8+ T‐cells are reduced in estrogen receptor (ER)+ tumors, suggesting different immunoregulatory patterns.
Both clonal selection and mass migration contribute to lymph node metastases in patients with ER+ cancer.
A large‐scale gene expression resource integrates diverse tissue samples and reveals unexpected heterogeneity of breast cancer subtypes.
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