Skin Tumor Initiation Research Articles

N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice

Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis.Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.

Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor.

The current paradigm holds that the inhibition of Rho guanosine nucleotide exchange factors (GEFs), the enzymes that stimulate Rho GTPases, can be a valuable therapeutic strategy to treat Rho-dependent tumors. However, formal validation of this idea using in vivo models is still missing. In this context, it is worth remembering that many Rho GEFs can mediate both catalysis-dependent and independent responses, thus raising the possibility that the inhibition of their catalytic activities might not be sufficient per se to block tumorigenic processes. On the other hand, the inhibition of these enzymes can trigger collateral side effects that could preclude the practical implementation of anti-GEF therapies. To address those issues, we have generated mouse models to mimic the effect of the systemic application of an inhibitor for the catalytic activity of the Rho GEF Vav2 at the organismal level. Our results indicate that lowering the catalytic activity of Vav2 below specific thresholds is sufficient to block skin tumor initiation, promotion, and progression. They also reveal that the negative side effects typically induced by the loss of Vav2 can be bypassed depending on the overall level of Vav2 inhibition achieved in vivo. These data underscore the pros and cons of anti-Rho GEF therapies for cancer treatment. They also support the idea that Vav2 could represent a viable drug target.

SFRP1 in Skin Tumor Initiation and Cancer Stem Cell Regulation with Potential Implications in Epithelial Cancers.

SummaryWnt signaling is involved in the regulation of cancer stem cells (CSCs); however, the molecular mechanism involved is still obscure. SFRP1, a Wnt inhibitor, is downregulated in various human cancers; however, its role in tumor initiation and CSC regulation remains unexplored. Here, we used a skin carcinogenesis model, which showed early tumor initiation in Sfrp1−/− (Sfrp1 knockout) mice and increased tumorigenic potential of Sfrp1−/− CSCs. Expression profiling on Sfrp1−/− CSCs showed upregulation of genes involved in epithelial to mesenchymal transition, stemness, proliferation, and metastasis. Further, SOX-2 and SFRP1 expression was validated in human skin cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma, and breast cancer. The data showed downregulation of SFRP1 and upregulation of SOX-2, establishing their inverse correlation. Importantly, we broadly uncover an inverse correlation of SFRP1 and SOX-2 in epithelial cancers that may be used as a potential prognostic marker in the management of cancer.

Establishment and Validation of an Ultra-Short-Term Skin Carcinogenicity Bioassay Using Tg-rasH2 Mice.

After initiation with 7,12-dimethylbenz[a]anthracene (DMBA), the promoting potential of 12-O-tetradecanoylphorbol-13-acetate (TPA) on skin tumor development can be detected by an ultra-short-term skin carcinogenicity bioassay using Tg-rasH2 mice. In the present study, 10 chemicals were assessed using this ultra-short-term bioassay as a first step to validate this practical and easy-to-use skin carcinogenicity bioassay. These chemicals belonged to 4 categories: dermal vehicles (acetone, 99.5% ethanol, anhydrous ethanol, and Vaseline), skin noncarcinogens (oleic acid diethanolamine condensate, benzethonium chloride, and diisopropylcarbodiimide), skin tumor promoters (TPA and benzoyl peroxide), and a skin carcinogen (4-vinyl-1-cyclohexene diepoxide). In a first study, DMBA was used as the initiator at a dose of 50 μg according to previous data, but skin tumors were observed in the no-treatment and vehicle groups. Therefore, the dose of DMBA for skin tumor initiation was reevaluated using 12.5 or 25 μg, with 12.5 μg found to be sufficient for initiation activity. In the ultra-short-term assay, the vehicles and skin noncarcinogens were negative while the skin tumor promoters and the skin carcinogen were positive. The detection of skin tumor promotion and carcinogenicity was feasible in only 8 weeks. In conclusion, this carcinogenicity bioassay may represent a useful tool for the assessment of the carcinogenicity potential of topically applied chemicals.

Abstract 4021: The evaluation of carcinogenicity evidence of dibenzanthracenes

Abstract Dibenzanthracenes (DBAs) are identified as carcinogens and are on the California Proposition 65 list. DBAs are five-ring polycyclic aromatic hydrocarbons (PAHs). This chemical group consists of three isomers: DB[a,c]A, DB[a,h]A, and DB[a,j]A. DBAs are products of the incomplete combustion or pyrolysis of organic matter and can be formed during high temperature cooking. They are air pollutants present in engine exhaust, tobacco and marijuana smoke, and may also contaminate soil and water. DB[a,h]A is a well-studied International Agency for Research on Cancer (IARC) Group 2A carcinogen, whereas fewer studies relevant to carcinogenicity have been conducted with DB[a,c]A and DB[a,j]A. Carcinogenicity evidence from multiple data streams was integrated in the hazard identification of this chemical group. These data streams include animal cancer bioassays, mechanistic studies and other relevant data, including high-throughput studies (e.g., ToxCast), toxicogenomic studies, and information from quantitative structure-activity relationship (QSAR) models. Structure activity comparisons across the three DBAs and related carcinogenic PAHs served to bridge the data gaps for the two less studied isomers. The results of our analyses showed that each of the DBAs share similar biological activities in animals: all induce tumors in mice, are mouse skin tumor initiators, form DNA adducts, are genotoxic, and form metabolites that are also genotoxic and initiators of mouse skin tumors. All three DBAs activate the aryl hydrocarbon receptor (AhR) in reporter gene assays, and DB[a,h]A and DB[a,c]A have been shown to bind to the AhR. In addition to strong evidence of genotoxicity, other carcinogenic mechanisms are likely also operative, including receptor activation (e.g., AhR), immune suppression, altered cell proliferation, apoptosis, and cell cycle regulation. There are strong structure-activity similarities among the DBAs and several carcinogenic 4-, 5- and 6-ring PAHs, including benzo[a]pyrene and dibenzo[a,h]pyrene. In addition, DB[a,c]A and DB[a,j]A were predicted to be mutagenic and carcinogenic in several QSAR models, including VEGA, Lazar and OECD QSAR Toolbox. Integration of the evidence from these multiple data streams resulted in the identification of the DBAs as a chemical group as carcinogens. Citation Format: Feng Tsai, Jennifer C. Hsieh, Gwendolyn Osborne, Martha Sandy. The evaluation of carcinogenicity evidence of dibenzanthracenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4021.

Shared and independent functions of aPKC\u03bb and Par3 in skin tumorigenesis

The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.

Abstract 4839: Ephrin-A ligands regulate cutaneous tumor etiology and metastasis through cell autonomous and non-autonomous mechanisms

Abstract Glycophosphatidylinositol-anchored ephrin-A ligands target EphA receptor tyrosine kinases (RTKs) to promote keratinocyte differentiation. Accordingly, genetic ablation of the major epidermal EphA subtype, EphA2, increases susceptibility to DMBA/TPA-induced cutaneous chemical carcinogenesis. Defining the corresponding role of ligands for EphA2 in skin cancer has been more cumbersome as the three ephrin-A genes (Efna1, Efna3, Efna4) are all prominently expressed in skin. We met this challenge by utilizing a triple Efna1/3/4 knockout (TKO) mice that reflects the pattern of reduced Efna gene expression found in mouse and human cutaneous SCCs. Skin tumors developed earlier and grew faster in mice lacking EphA2 or these three ephrin-A ligands. Interestingly TKO mice displayed accelerated malignant progression toward invasive SCC that metastasized to the lymph nodes and lungs by 25 weeks following DMBA-TPA treatment. Using keratinocyte culture models, we found that ephrin-A ligands act within the epidermis to limit keratinocyte migration in a manner that depends on their targeting of EphA2. We also illustrated a key role for ephrin-A ligands in the surrounding tumor microenvironment by re-introducing isogenic SCC cell lines into the skin of wild-type or TKO mice on congenic FVB background; tumor growth and metastasis was facilitated in mice lacking ephrin-A ligands. Importantly, the invasive phenotype of TKO mouse tumor cell lines was normalized by genetic reintroduction of either Efna1 or Efna3. Integrating our findings from human tumors, mouse models, primary cell cultures, and allograft models provides strong support for the notion that ephrins operate within tumor cells and also in the microenvironment to suppress skin tumor initiation and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Ji Zheng, Bethany Perez White, Nihal Kaplan, Zhe Zhao, Miroslav Blumenberg, Spiro Getsios, Bingcheng Wang. Ephrin-A ligands regulate cutaneous tumor etiology and metastasis through cell autonomous and non-autonomous mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4839. doi:10.1158/1538-7445.AM2017-4839

506 Molecular mechanisms of p53 activity in stem cell-driven skin tumour initiation

TP53 (p53) is the most frequently mutated gene and altered in approximately 50% of human cancer leading to loss or aberrant activation of p53. Tumours lacking p53 mutations often display inactivated wild-type p53 due to modulation of protein interactions resulting in p53 degradation. Functionally, p53 acts as an essential transcriptional factor controlling the response to several different cellular stresses including DNA damage, hypoxia and oncogene activation. It is well known that common environmental assaults, including UV irradiation cause p53 modifications, promoting tumorigenesis in mammalian skin. Increasing evidence suggest that restoring normal p53 function will be highly beneficial for cancer therapy. Therefore, it is important to gain better insights into the regulation of p53 stability in the context of oncogenic mutations in skin cancer. In this context, our previous work uncovered important stem cell-specific functions of p53 protecting from tumour initiation and guaranteeing tissue maintenance. Here, we decipher the underlying molecular mechanism of p53-induced stem cell responses and explore the mechanistic link between p53 and b-catenin/Lef1 interaction in stem cell-driven skin cancer. Using a transgenic mouse model for mutant Lef1-driven tumourigenesis, thereby mimicking Lef1 mutations found in human skin tumours, we demonstrate that mutant Lef1 induces tumours by interfering with stem cell-specific gatekeeper functions normally preventing tumour initiation. Mechanistically, mutant Lef1 disturbs p53 responses by antagonizing ATM-Chk2-dependent p53 stabilization. Most importantly, modulating the level of p53 activity in the context of tumour initiation had a great impact on the cell-of-origin and the phenotype of epidermal tumours. In conclusion, our work identified novel aspects of p53 in stem cell-driven skin tumour initiation, is providing new mechanistic insights into p53 activity and is connecting p53 and b-catenin/Lef1 signalling and thus addresses important issues highly relevant for translational skin research.

Deoxynivalenol induced mouse skin tumor initiation: Elucidation of molecular mechanisms in human HaCaT keratinocytes.

Among food contaminants, mycotoxins are toxic to both human and animal health. Our prior studies suggest that Deoxynivalenol (DON), a mycotoxin, behaves as a tumor promoter by inducing edema, hyperplasia, ODC activity and activation of MAPK's in mouse skin. In this study, topical application of DON, 336 and 672 nmol significantly enhanced ROS levels, DNA damage and apoptosis with concomitant downregulation of Ki-67, cyclin D, cyclin E, cyclin A and cyclin-dependent kinases (CDK4 and CDK2) thereby resulting in tumor initiation in mouse skin. Further, the elucidation of molecular mechanisms of tumor initiation by DON (0.42-3.37 nmol/ml) in HaCaT keratinocytes, revealed (i) enhanced ROS generation with cell cycle phase arrest in G0/G1 phase, (ii) increase in levels of 8-OxoG (6-24 hr) and γH2AX protein, (iii) significant enhancement in oxidative stress marker enzymes LPO, GSH, GR with concomitant decrease in antioxidant enzymes catalase, GPx, GST, SOD and mitochondrial membrane potential after DON (1.68 nmol) treatment, (iv) suppression of Nrf2 translocation to nucleus, enhanced phosphorylation with subsequent activation ERK1/2, p38 and JNK MAPK's following DON (1.68 nmol) treatment, (v) overexpression of c-jun, c-fos proteins, upregulation of Bax along with downregulation of Bcl-2 proteins, (vi) increase in cytochrome-c, caspase-9, caspase-3 and poly ADP ribose polymerase levels leads to apoptosis. Pretreatment of superoxide dismutase, mannitol and ethanol to HaCaT cells resulted in significant reduction in ROS levels and apoptosis indicating the role of superoxide and hydroxyl radicals in DON induced apoptosis as an early event and skin tumor initiation as a late event.

Defining the clonal dynamics leading to mouse skin tumour initiation.

The changes that occur in cell dynamics following oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the impact of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, were competent to initiate tumour formation upon oncogenic hedgehog signalling. Interestingly, this difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase of symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is not only dependent on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin.

Lgr5+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors

Actively proliferating Lgr5+ skin stem cells are found deep in the hair follicle (HF). These cells renew the HF and drive its expansion in anagen phase. Their long residence and continuous mitotic activity make them prime candidates to transform into skin tumor-initiating cells. This was investigated by subjecting Lgr5-EGFP-Ires-CreERT2/R26R-LacZ mice (haired and hairless) to chemical and UV carcinogenic regimens. In the course of these regimens Lgr5+ cells (EGFP+) remained exclusively located in HFs, and in deep-seated cysts of hairless skin. In haired mice, progeny of Lgr5+ stem cells (LacZ+ after a pulse of tamoxifen) appeared in the interfollicular epidermis upon UV-induced sunburn and in TPA-induced hyperplasia. In hairless mice the progeny remained located in deep-seated cysts and in HF remnants. Progeny in hairless skin was only detected interfollicularly at a late stage, in between outgrowing tumors. Lgr5+ stem cells were absent in the ultimate tumor masses, and no tumor appeared to be a (clonal) expansion of Lgr5+ cells (52 tumors with tamoxifen at the start of carcinogenesis, 42 tumors with tamoxifen late during tumor outgrowth). In contrast to CD34/K15+ quiescent bulge stem cells, actively proliferating Lgr5+ stem cells do therefore not appear to be tumor drivers in experimental skin carcinogenesis.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Different Levels of Twist1 Regulate Skin Tumor Initiation, Stemness, and Progression

Twist1 promotes epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and cancer stem cell (CSC) properties. However, it remains unclear whether Twist1 is also required for tumor initiation and whether Twist1-induced cancer stemness and EMT are functionally linked. Using a conditional deletion of Twist1 at different stages of skin carcinogenesis, we show that Twist1 is required for skin tumor initiation and progression in a gene-dosage-dependent manner. Moreover, conditional ablation of Twist1 in benign tumors leads to increased apoptosis, reduced cell proliferation, and defective tumor maintenance and propagation independently of its EMT-inducing abilities. Concomitant deletion of Twist1 and p53 rescues the apoptotic response, but not the cell proliferation and propagation defects. These results reveal that Twist1 is required for tumor initiation and maintenance in a p53-dependent and -independent manner. Importantly, our findings also indicate that tumor stemness and EMT can be regulated by distinct mechanisms.

MiR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival.

Previously, we identified miR-125b as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans, miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. We further show that miR-125b can confer "oncomiR addiction" in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated miR125b targets that are specifically associated with tumors that are dependent on miR-125b. Through molecular and genetic analysis of these targets, we uncovered new insights underlying miR-125b's oncogenic function. Specifically, we show that, on the one hand, mir-125b directly represses stress-responsive MAP kinase genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing Vps4b (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate miR-125b as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.

Vav Proteins' Role in Skin Cancer

Vav Proteins' Role in Skin Cancer

The Rho exchange factors Vav2 and Vav3 favor skin tumor initiation and promotion by engaging extracellular signaling loops.

Author SummaryGDP/GTP exchange factors (GEFs) involved in Rho GTPase activation have been traditionally considered as potential anticancer drug targets. However, little is known about the best GEFs to inhibit in different tumor types, the pro-tumorigenic programs that they regulate, and the collateral effects that inactivation may induce in healthy tissues. Here, we investigate this issue in HRas-dependent skin tumors using genetic techniques. Despite the large number of Rho GEFs present in both normal and tumoral epidermis, we demonstrate that the co-expression of the exchange factors Vav2 and Vav3 is critical for the development of this tumor type. We also identify a previously unknown Vav-dependent autocrine/paracrine program that favors keratinocyte survival/proliferation and the formation of an inflammatory state during the initiation and promotion phases of this tumor. Finally, our results indicate that inactivation of Vav proteins is innocuous for the homeostasis of normal epidermis. Taken together, these results imply that Vav protein-based therapies may be of interest for skin tumor prevention and/or treatment.

Effective Inhibition of Skin Cancer, Tyrosinase, and Antioxidative Properties by Astaxanthin and Astaxanthin Esters from the Green Alga Haematococcus pluvialis

Astaxanthin mono- (AXME) and diesters (AXDE) were characterized and examined for anticancer potency with total carotenoids (TC) and astaxanthin (AX) against UV-7,12-dimethylbenz(a)anthracene (DMBA)-induced skin cancer model in rat. At 200 μg/kg bw, AXDE and AXME reduced UV-DMBA-induced tumor incidences up to 96 and 88%, respectively, when compared to AX (66%) and TC (85%). UV-DMBA has been known to generate high levels of free radicals and tyrosinase enzyme, leading to characteristic symptoms of skin pigmentation and tumor initiation. Intriguingly, ~7-fold increase in tyrosinase and 10-fold decrease in antioxidant levels were normalized by AXDE and AXME as opposed to only ~1.4-2.2-fold by AX and TC, respectively. This result together with the appearance of 72 and 58 ng/mL of retinol in the serum of respective AXE-treated (AXDE + AXME) and AX-treated animals suggested that better anticancer potency of AXEs could be due to increased bioavailability.

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Stem Cell Dynamics and Heterogeneity: Implications for Epidermal Regeneration and Skin Cancer

The skin epithelium undergoes constant renewal, a process that is driven by stem cells (SCs) localising to the interfollicular epidermis and different regions of the hair follicle. Over the last years, tremendous progress has been made to unravel the physiological function of distinct stem and progenitor cell populations by using genetic lineage tracing in vivo, transplantation, clonogenicity approaches and live cell imaging. It turned out that these cell compartments constitute heterogeneous SC pools and that individual SCs respond differently to various signals sent by the microenvironment. Recent genetic manipulation experiments and elegant mouse models have shed light on the signalling pathways being crucial for self-renewal and lineage fate decisions during tissue homeostasis. Here, we summarise current concepts of SC function in mammalian skin and focus on the dynamic behaviour of SCs during morphogenesis and tissue regeneration of the skin epithelium. Clearly, understanding the cellular and molecular mechanisms of SC regulation and function during tissue homeostasis has enormous impact on our view of the pathogenesis of various skin diseases and will be beneficial for regenerative medicine. Recent experiments suggest an important role of tissue SCs in the process of skin tumour initiation and progression. For the future, the genuine challenge is to further dissect SC function in pathophysiological settings and to translate our knowledge to design novel efficient therapeutic strategies for treatment of cutaneous cancer.

Stem Cell Dynamics and Heterogeneity: Implications for Epidermal Regeneration and Skin Cancer

The skin epithelium undergoes constant renewal, a process that is driven by stem cells (SCs) localising to the interfollicular epidermis and different regions of the hair follicle. Over the last years, tremendous progress has been made to unravel the physiological function of distinct stem and progenitor cell populations by using genetic lineage tracing in vivo, transplantation, clonogenicity approaches and live cell imaging. It turned out that these cell compartments constitute heterogeneous SC pools and that individual SCs respond differently to various signals sent by the microenvironment. Recent genetic manipulation experiments and elegant mouse models have shed light on the signalling pathways being crucial for self-renewal and lineage fate decisions during tissue homeostasis. Here, we summarise current concepts of SC function in mammalian skin and focus on the dynamic behaviour of SCs during morphogenesis and tissue regeneration of the skin epithelium. Clearly, understanding the cellular and molecular mechanisms of SC regulation and function during tissue homeostasis has enormous impact on our view of the pathogenesis of various skin diseases and will be beneficial for regenerative medicine. Recent experiments suggest an important role of tissue SCs in the process of skin tumour initiation and progression. For the future, the genuine challenge is to further dissect SC function in pathophysiological settings and to translate our knowledge to design novel efficient therapeutic strategies for treatment of cutaneous cancer.