How Aging Stem Cells Can Lead to Cancer Development

Table of Contents

• Introduction: The Mystery of Stem Cells and Cancer
• Understanding Stem Cells and Their Role in the Body
• How Precancer Stem Cells Develop and Evolve
• Specific Mechanisms in Blood Cancers and Leukemias
• The Sequence of Genetic Changes in Cancer Development
• How Inflammation and Aging Accelerate Cancer Risk
• What This Means for Cancer Prevention and Treatment
• What We Still Don't Know About This Process
• Recommendations for Patients and Future Research
• Source Information

Introduction: The Mystery of Stem Cells and Cancer

Stem cells represent one of the most fascinating and mysterious aspects of human biology. Like the ancient philosophical question about existence itself, stem cells may remain dormant throughout a person's lifetime without ever fulfilling their potential, or they may differentiate into other cell types and cease being stem cells altogether.

The most unique property of stem cells is their ability to divide without differentiating, a process called self-renewal. This allows them to continuously generate all cells in a tissue while maintaining a pool of stem cells. However, when this self-renewal process becomes deregulated during aging or in response to environmental stressors, it can lead to cancer development.

All cells in the body can acquire mutations, but without self-renewal capability, they cannot become the roots of cancer. The research shows that precancer stem cells arise from mutated tissue stem cells that disrupt normal tissue balance, particularly evident in blood-forming stem cells involved in preleukemic bone marrow disorders.

Understanding Stem Cells and Their Role in the Body

Stem cells are the foundation cells for all tissues in our bodies. Only hematopoietic stem cells (HSCs), or blood-forming stem cells, can regenerate blood formation for life in transplant recipients. These remarkable cells represent only approximately 1 in 100,000 bone marrow cells and slowly circulate between bone marrow and blood.

Research has identified at least two main populations of HSCs that exist after birth: balanced and lymphoid-biased HSCs that dominate in early life, and myeloid-biased HSCs that become more prevalent in old age. The aging process accelerates HSC aging through acquisition of somatic DNA mutations earlier in life through a process called clonal hematopoiesis.

Between cell divisions, HSCs can accumulate mutations that cause DNA strand breaks. When these cells enter the cell cycle, most DNA repair systems activate, with entry into the replication phase occurring approximately 30 hours after cell-cycle entry begins. The types of genes expressed at higher levels in HSCs from aged mice are often the same genes involved in human leukemia development.

How Precancer Stem Cells Develop and Evolve

Precancer stem cells develop through a complex process involving both intrinsic factors within the cells themselves and extrinsic factors from their environment. These cells give rise to expanded progenitor populations and can undergo malignant transformation and immune evasion, which promotes the propagation of malignant stem cells.

In myeloproliferative neoplasms and myelodysplastic syndromes (types of blood disorders), preleukemia stem cells acquire several dangerous capabilities:

• Resistance to apoptosis (programmed cell death)
• Assurance of longevity
• Evasion of innate and adaptive immune responses

These changes ultimately lead to the generation of self-renewing leukemia stem cells that fuel therapeutic resistance in secondary acute myeloid leukemia (AML), partly by becoming dormant in protective microenvironments. Because cancer stem cells drive resistance to therapy, intercepting their generation from precancer stem cells may become an effective strategy for achieving durable remissions.

Specific Mechanisms in Blood Cancers and Leukemias

The research provides detailed insights into how specific blood cancers develop. In chronic myeloid leukemia (CML), preleukemia cells arise at the HSC stage amid inflammatory cytokine up-regulation in the stem cell environment. The emerging myeloid blast crisis cells are daughter cells of the clone at the granulocyte-monocyte progenitor stage.

These cells typically have translocated β-catenin (a self-renewal agonist) to the nucleus and have misspliced exon 8 kinase domain out of GSK3β (glycogen synthase kinase 3 beta). This missplicing allows unphosphorylated β-catenin to enter the nucleus and become a self-renewal–inducing transcription factor.

Malignant reprogramming of human preleukemia myeloid progenitors into self-renewing leukemia stem cells is accelerated by prosurvival splicing deregulation and inflammatory cytokine–driven activation of the RNA-editing enzyme ADAR1p150. Specifically, ADAR1p150 overexpression reduces self-renewal regulatory microRNA biogenesis and tumor suppression while altering cell-cycle transit.

In myelodysplastic syndromes, most HSCs belong to a single clone derived from one cell, some with chromosomal anomalies that cause the disease. At the progenitor stage, these cells express "eat me" signals that lead to phagocytic removal of blood cell precursors, causing bone marrow failure disorders.

The Sequence of Genetic Changes in Cancer Development

The research reveals that the order of mutations in cancer development is not random, despite mutational processes being random themselves. In more than 30 cases of AML examined, epigenetic regulators that control chromatin opening and closing initiated the successful HSC clone.

The final events that drove the preleukemia clone into leukemia stem cells were classical oncogenes including:

1. NRAS mutations
2. KRAS mutations
3. FLT3-ITD mutations

These oncogenes were almost always the last mutations acquired and were associated with the preleukemia HSC clone transitioning to a downstream multipotent progenitor or granulocyte-macrophage progenitor leukemia stem cell. The clones also up-regulate antiphagocytic CD47 and counter the prophagocytic calreticulin signal, which appears to be a permanent epigenetic change.

CD47 up-regulation occurs late in precancer development and "saves" the clones from programmed cell removal. This up-regulation of "don't eat me" signals allows single tissue stem cells to undergo genetic and epigenetic changes and expand clonally, contributing to hematologic cancers.

How Inflammation and Aging Accelerate Cancer Risk

In addition to radiation and toxic exposure-induced DNA damage, "inflammaging" may lead to clonal hematopoiesis and precancer stem cell generation. Chronic inflammation has long been linked to accelerated tissue aging, particularly in the blood-forming system.

Inflammaging is a process induced by prolonged inflammatory cytokine signaling that promotes accelerated stem-cell aging and precancer stem-cell generation. Both environmental and microenvironmental drivers of inflammaging in HSCs and other tissue-specific stem cells have emerged as major factors in precancer stem-cell generation.

Aging is associated with several immune changes that affect cancer surveillance:

• Decreased neutrophil respiratory burst
• Decline in macrophage production of toll-like receptors
• Reduced chemokine and cytokine production
• Decreased T-cell proliferative potential
• Reduced natural killer-cell activity

However, other aspects of immunity increase with aging, evidenced by increased production of proinflammatory cytokines by blood cells from older persons compared with younger individuals. Chronic immune activation is associated with systemic signaling driven by proinflammatory cytokines including TNF-α, interferons, and interleukins 1 and 6.

What This Means for Cancer Prevention and Treatment

This research has significant implications for cancer prevention and treatment strategies. Since cancer stem cells fuel resistance to therapy, intercepting the generation of cancer stem cells from precancer stem cells may become an effective strategy for inducing durable remissions.

Successful interception strategies will depend on determining whether tissues with functionally defined stem cells form precancer stem-cell clones, understanding the clonal hierarchies that drive precancer stem cell evolution in different tissues, and searching for diseases caused by clones that haven't fully transformed into invasive cancer.

The identification of specific enzymes and pathways involved in precancer development, such as ADAR1 and APOBEC3, provides potential targets for therapeutic intervention. Research shows that in 20 different cancers, ADAR1 has been linked to immune evasion and resistance to therapy.

Another gene active during embryonic development, ROR1, has also been linked to cancer stem-cell self-renewal and early relapse after therapy, with high expression in chronic lymphocytic leukemia cells conferring a poor prognosis.

What We Still Don't Know About This Process

Despite these significant findings, important questions remain unanswered. Advanced age– and systemic inflammation–related mechanisms governing the generation of precancer stem cells and their malignant transformation remain mysterious in many human cancers.

The role of stem-cell inflammaging in the loss of tissue homeostasis and precancer development has not been clearly elucidated. While host immune responses evolved to protect stem cells and other cells involved in tissue homeostasis, chronic immune activation's precise role in cancer development needs further investigation.

Additionally, more research is needed to understand how evasion of programmed cell removal occurs in HSCs and whether similar processes occur in other tissue stem cells, potentially causing other cancers and diseases beyond blood disorders.

Recommendations for Patients and Future Research

For patients, this research underscores the importance of managing chronic inflammation and understanding individual cancer risk factors, particularly as we age. While more research is needed, maintaining overall health and reducing inflammatory processes through lifestyle factors may help reduce cancer risk.

For researchers and clinicians, several priorities emerge:

1. Develop better methods for detecting precancer stem cells before full transformation occurs
2. Create interventions that target specific enzymes like ADAR1 and APOBEC3 that drive cancer evolution
3. Explore immunotherapy approaches that address the immune evasion capabilities of precancer cells
4. Investigate how to modulate the stem cell environment to prevent malignant transformation

The findings also suggest that personalized medicine approaches that account for an individual's specific mutation sequence and inflammatory environment may be particularly effective for preventing and treating cancers that originate from stem cell mutations.

Source Information

Original Article Title: Stem-Cell Aging and Pathways to Precancer Evolution

Authors: Catriona H.M. Jamieson, M.D., Ph.D., and Irving L. Weissman, M.D.

Publication: The New England Journal of Medicine, October 5, 2023

DOI: 10.1056/NEJMra2304431

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine and preserves all significant findings, data, and conclusions from the original scientific publication.