Epidermal stem cells and cancer stem cells: Insights into cancer and potential therapeutic strategies
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
Section snippets
p63 and epidermal stem cells
Several groups independently identified the third member of the p53 family, p63, also known as p51, KET, p40, p73L, p53CP and NBP. p63 was later shown to be crucial in the development of all epithelial tissues.23 The expression profile of the p63αΔN isoform was demonstrated to represent the holoclone population of cells present within the epidermis.11 p63 exhibits a rather tissue-specific distribution pattern and is highly expressed in the ectodermal surfaces of the limb buds, branchial arches
p63 over-expression in many tumours: putative cancer stem cells?
Over-expression of select p63 splice variants is observed in many squamous carcinomas, suggesting that p63 may act as a proto-oncogene.44 The use of various model systems and the study of human disease should continue to lead to rapid advances in our understanding of the role of p63 in development, epithelial cell maintenance and tumourigenesis. The existence of cancer stem cells has been demonstrated in many tumour classes of different tissue origins. A study of human skin cancers revealed
p63 stem cell regulation and p53 tumour suppression: ‘archangels’ of life and death
UV radiation emitted by the sun is a major carcinogen (both initiator and promoter) for most skin cancers.12, 53 Pro-carcinogenic effects of UV-light may be blocked by three distinct, but potentially interrelated, cellular responses involving epidermal keratinocyte stem cells, namely (i) DNA repair; (ii) apoptosis; and (iii) senescence (terminal differentiation). One of the most widely studied responses to UV light is for DNA-damaged keratinocytes to be eliminated via apoptosis, a process
Strategies to eradicate cancer stem cells
New insights into the exploitation of targeted therapy towards populations of cancer cells that maintain the ability to form a cancer are being investigated worldwide. One of the hallmarks of cancer that is coming to light is that many tumours possess a population of cancer cell progenitors that repopulate the tumour mass as proportions of the cell populous undergo a differentiation process and subsequent apoptosis (known as ‘cancer cell turnover’). Cancer stem cell progenitors are perhaps of
Conclusion
From the data provided here one can propose key questions to be addressed:
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Do the selective pressures that occur during cancer development require p63αΔN in all cases of epithelial cancer progression?
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What effect does down-regulation of p63αΔN have on cancer cells that have high levels of p63?
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Can cancer cells compensate for loss of p63αΔN expression under the selective pressures they face?
One could say with confidence that the answers will be complex and will not be the same for every form of
Conflict of interest statement
None declared.
Acknowledgements
The authors thank the British Skin Foundation for funding LEF, and acknowledge the expert assistance of the Tayside Tissue Bank (Dundee), funded by the MRC/CRUK partnership, for contributions to the processing and staining of skin sections shown here (in particular George Thomson), and Maya El Baltagi (MSc Student) for experimental assistance. The authors thank James DiRenzo for his plasmid DNA and discussions.
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Drug discovery and mutant p53
2010, Trends in Cell BiologyCitation Excerpt :Indeed, the signaling events that inhibit p63 function in turn include a RAS-CK1 cascade that can stabilize the mutant p53 PPI with SMAD2. However, these data cannot yet be reconciled due to the fact that transgenic pro-oncogenic p53s encoded by the mouse equivalent of the R175H allele do not have developmental defects similar to those seen in p63-null animals [31]. These data suggest that mutant p53 inhibition of p63 might be confined to selected cancer cells and is not necessarily fundamental to mutant p53 function.
Contemporary pre-clinical development of anticancer agents - What are the optimal preclinical models?
2009, European Journal of CancerCitation Excerpt :The uses of isogenic cell lines with defined deficiency of each mechanism of DNA repair are available and very useful in defining the mode of action of new anticancer drugs.15–17 The recently put forward cancer stem cell hypothesis states that a minority of tumour cells (the cancer stem cells or tumour initiating cells - TIC - usually defined by cell surface marker expression) are responsible for tumour initiation, propagation and recurrence.18–20 This hypothesis has important implications as the goal of the therapy is to specifically eradicate these cells.21–23
Sebaceous neoplasia and Torre-Muir syndrome
2007, Current Diagnostic PathologyTumour-initiating cells vs. cancer 'stem' cells and CD133: What's in the name?
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