Epidermal stem cells and cancer stem cells: Insights into cancer and potential therapeutic strategies

Abstract

Epithelial keratinocyte regeneration has been exemplified as dependent on a population of cellular progenitors that have retained developmental pluripotency, a latent capacity for proliferation and differentiation with a prolonged lifespan. Recent evidence suggests that the cell populations that regulate the development of normal tissues, and which play vital roles in maintaining the overall homeostasis of the tissue, might be the key target population that is essential for malignant cancer development, thus giving rise to the notion of ‘cancer stem cells’. This review examines the leading research into the relationship between adult stem cells in human skin marked by p63αΔN, their putative importance in cancer development, and how we might exploit our evolving knowledge of adult tissue stem cells to aid cancer treatments in the future. Furthermore, the review examines information regarding ataxia telangiectasia mutated (ATM) kinase and key regulatory events that take place on p53, only within putative keratinocyte stem cells that are transcriptionally regulated by p63αΔN.

Introduction

The epidermis is a protective barrier subject to an array of genotoxic insults known to be involved in tumourigenesis. Subsequent regenerative cycles depend on a subset of epithelial precursors that resist terminal differentiation and retain their potency for proliferative capacity,¹ namely stem cells. The identification of this subset of stem cells represents an important step towards understanding the events that regulate cellular differentiation of epithelia and the consequences of their subversion. Furthermore, the elucidation of the cell population that is at risk of becoming cancerous is likely to be important in the development of effective therapies. Some of the phenotypes of cancer are similar to the qualities attributed to adult tissue stem cells. The first clues towards the notion of stem cells being the cancerous target were described by cell biologists nearly 30 years ago.² Since then, keratinocyte subpopulations have been found to be highly susceptible to the acquisition of oncogenic mutations.3, 4 However, only a small number of skin cancers develop, as most cells acquire mutations that are lost through the normal process of terminal differentiation, which acts a cellular proof-reading mechanism. It has been demonstrated that more than one genetic lesion is required to cause a sustainable tumour. The majority of tumours are clonal in their origin and it has been estimated that 3–5 genetic events in humans and 2–3 in rodents are necessary to transform a normal cell into a cancer cell.5, 6 Thereby, the long-term residents of the epidermis, such as stem cells, are possibly the only cells that have the ability to accumulate the number of genetic hits necessary to result in tumour formation while remaining viable.⁷

Skin stem cells have been described as either unipotent, implying that they generate a single lineage, or multipotent, meaning that they generate multiple lineages (pluripotent stem cells have not been identified in skin). Skin stem cells usually divide infrequently (slow cycling) to generate either two daughter stem cells that are identical to the founding stem cell (symmetrical division) or one daughter cell identical to the founding stem cell and one with differing capacity (asymmetrical division).8, 9 Elegant studies by Barrandon and colleagues selectively demonstrated that three classes of the epidermal keratinocyte populations comprise the epidermis and that only one class had a true potential to form large colonies, indicated by a high proliferative capacity. The three classes of cells described were holoclones (stem cell-like), meroclones (transit amplifying (TA) cells) and paraclones (terminally differentiated cells), respectively.¹⁰ Treatment with a known carcinogenic stimulus did not culminate in each class liberating cancerous cells. The only class that had the ability to form viable, highly proliferative genetically damaged cells were the holoclones, now known to have stem cell populations.¹¹ Another example was shown when it was reported that ultraviolet (UV) light induced TP53 mutations in human interfollicular epidermis.¹² Numerous cells with TP53 mutations were found in sun-exposed, but clinically normal, human epidermis. Both scattered single cells and clonal patches of mutated TP53-positive cells were observed throughout the exposed epidermis.13, 14, 15, 16 The location of large patches of TP53 mutated cells was found to be selective for stem-cell-rich regions, exemplifying that epidermal stem cells maybe be the only cells that have the capacity substantially to propagate UV-light-induced genetic alterations.⁷ The selective survival of epidermal stem cells is not thought to lead directly to cancer, but their progeny have a greater risk of accumulating the further genetic modifications within key tumour suppressor genes that are required to induce tumour formation.

Further discoveries in cancer biology demonstrate that lesions arise from stem cells by selective mutagenic events creating the formation of cancer stem cells that then go on to constitute the formation of a tumour. In these models, cancer stems cells do not represent a majority of the cells within a tumour, but are nevertheless critical for its propagation. Evidence for this is that tumours have also been reported to undergo a differentiation process, giving rise to both TA cells and terminally differentiating cells, which are genetically altered. Many reports of cancers possessing differentiated cell types have long been documented in a wide compendium of solid tumours.¹⁷ The concept of cancer stem cells dates back almost as far as the discovery of somatic stem cells in the haematopoietic system, the skin and gastrointestinal tract crypts.18, 19 There is in vitro evidence that demonstrates that cell populations that are not stem-cell-like can give rise to increased proliferative capacity when an oncogene is artificially over-expressed.²⁰ This suggests that stem cell populations may not be the only cells capable of undergoing transformation, but that TA cells can also form tumours.²⁰ However, it is unclear if these cells are immortal and/or have the capacity to develop full-blown malignancy. It is possible that these cell types can only form benign conditions, which would suggest that they lack the proliferative potency required for malignant disease. Importantly, the results of these experiments do not deny the notion of stem cells being the precursor cells targeted during carcinogenesis, but reveal the further importance to our understanding of completely elucidating the origins of cancer development. Other studies suggest that the make-up of the extracellular matrix has a dramatic effect on the differentiation profiles of cells, and that papillomas can be generated from differentiated keratinocytes.²¹ It is not known whether these populations revert to TA cells or stem cells, but it has been revealed that recapitulation of the stem cell niche is important in cancer development.²² So far, p63αΔN and integrin 1β are the most widely reported biological markers that have been demonstrated robustly and singularly to identify unipotent stem cells.²¹