p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome

Abstract

p53 is well recognized as a potent tumor suppressor. In its classic role, p53 responds to genotoxic insults by inducing cell cycle exit or programmed cell death to limit the propagation of cells with corrupted genomes. p53 is also implicated in a variety of other cellular processes in which its involvement is less well understood including self-renewal, differentiation, and reprogramming. These activities represent an emerging area of intense interest for cancer biologists, as they provide potential mechanistic links between p53 loss and the stem cell-like cellular plasticity that has been suggested to contribute to tumor cell heterogeneity and to drive tumor progression. Despite accumulating evidence linking p53 loss to stem-like phenotypes in cancer, it is not yet understood how p53 contributes to acquisition of "stemness" at the molecular level. Whether and how stem-like cells confer survival advantages to propagate the tumor also remain to be resolved. Furthermore, although it seems reasonable that the combination of p53 deficiency and the stem-like state could contribute to the genesis of cancers that are refractory to treatment, direct linkages and mechanistic underpinnings remain under investigation. Here, we discuss recent findings supporting the connection between p53 loss and the emergence of tumor cells bearing functional and molecular similarities to stem cells. We address several potential molecular and cellular mechanisms that may contribute to this link, and we discuss implications of these findings for the way we think about cancer progression.

Keywords: cancer; dedifferentiation; p53; plasticity; reprogramming; stem cell.

Figure 1.

The p53 pathway in development, cancer, and reprogramming. A select set of p53 upstream regulators and downstream effectors are shown in the context of p53-dependent plasticity and self-renewal. The involvement of pathway members in development, cancer, or reprogramming is indicated by their adjacent color-coded squares. Whether induced plasticity leads to induced pluripotent stem cells or stem-like cancer cells may depend on the extent or reversibility of oncogene activation, p53 inactivation, or microenvironmental factor.

Figure 2.

Impact of stem cell state on p53 activation and differentiation. In this model, stem cell populations can be heterogeneous, with some being more responsive to p53 activation. Various stresses can activate p53 to induce differentiation or apoptosis in the sensitive stem, while insensitive cells with dampened p53 responses survive and may proliferate in response to paracrine signals such as Wnt. This model is compatible with recent reports of multiple pluripotent stem cell states in embryonic stem cell cultures^, and that multipotent progenitors in the hematopoietic compartment act as stem cells if p53 activation is abrogated in conjunction with Ink4a/ARF deletion.

Figure 3.

Models of stem cell state acquisition in cancer. (A) A model of the classic differentiation hierarchy initiated by a self-renewing stem cell (A-i). Tumorigenic transformation occurs within a self-renewing stem cell (A-ii). Mutations engender self-renewal competence in a progenitor cell (A-iii). (B) In normal tissues, p53 function limits the possibility of reprogramming to a stem-like state (B-i). Cancer-associated reprogramming following p53 inactivation would permit the evolution of a stem-like cancer from stem or non–stem cell antecedents (B-ii). It is also possible that reprogramming could drive cells toward even more primitive embryonic stem cell states, as occurs in the reprogramming of differentiated cells to induced pluripotent cells (B-iii). SC = stem cell.

Figure 4.

Induced plasticity in cancer and the potential for multiple cancer stem-like cells to coexist. A tumor mass (left) may contain multiple related but genetically distinct and independently propagating clones (A and B). Each clone may be sustained by a genetically and epigenetically unstable pool of stem-like cells (right), whose behavior (e.g., proliferation v. dormancy) can be influenced by the level and nature of oncogenic stimuli and the dissimilar local microenvironment in which they are situated. While some stem cells may initiate or perpetuate clonal growth in response to local microenvironments, other stem-like cells may remain indolent until appropriate signals are received. The resulting heterogeneity may be manifested as diverse stem-like states that vary in terms of their proliferative, biomarker, and chemosensitivity profiles as well as their ability to xenograft but not in their net tumorigenicity. Furthermore, disaggregation of the tumor mass for analysis obscures the local heterogeneity initially present. Together, inherent plasticity as well as additional acquired genetic traits may endow these cells with differential capacities for interconversion to more aggressive stem-like states during tumor evolution or recurrence.