Linking stem cells to chromosomal instability

Abstract

The discovery of a stem cell population in human neoplasias has given a new impulse to the study of the origins of cancer. The tissue compartment in which transformation first occurs likely comprises stem cells, since these cells need to consolidate the short-term and long-term requisites of tissue renewal. Because of their unique role, stem cells have a combination of characteristics that makes them susceptible to genetic damage, transformation, and tumor initiation. One type of genetic damage in particular, chromosomal instability, might affect the stem cell compartment, because it induces an ongoing cycle of DNA damage and alters cellular programming. Here, we will discuss some of the recently described links between SC, chromosomal instability, and carcinogenesis, and outline some of the consequences for oncoimmunology.

Figure 1.

The role of stem cells in cancer. Whereas normal tissue homeostasis requires the coordination of the proliferation of stem and progenitor cells with their differentiation (above), cancer-inducing defects (*) are thought to inhibit stem cell differentiation (below). The resulting accumulation of progenitor cells with a residual capacity to proliferate allows for additional mutations (#, ≈), which promote further tumor growth and heterogeneity. Theories that propose the dedifferentiation of fully differentiated cells have lost importance in the last years.

Figure 2.

CSC and cancer therapy. In heterogeneous primary tumors, more differentiated cells (white) have been shown to be susceptible to treatment, such as radiation or chemotherapy. CSC (gray) however are more resistant to currently used treatments, and might be responsible for tumor recurrence and ongoing chromosomal instability if not eliminated efficiently. Immunological strategies that directly target the CSC that are more resistant to classical therapies might thus help to ensure complete eradication of cancer cells.

Figure 3.

Stem cell characteristics favor tumor development. A combination of stem cell properties (boxes), essential for their role in tissue renewal, contributes to the long-term accumulation of cells bearing genetic defects (arrows). A sustained mitotic rate in combination with highly active break repair and resistance to apoptosis are important to avoid stem cell depletion. These factors however promote chromosomal instability after accidental breakage and fusion of centromere-containing chromosome arms, resulting in the survival of genetically imbalanced cells. Elimination of cancer cells by the immune system (dashed arrows) might be ineffective as a consequence of stem cell immunosuppressive capacity. Once chromosomal instability is initiated, it promotes a self-amplifying cycle of gene dosage and reduced apoptosis (dotted arrows) through the duplication and deletion of genomic segments.